Patent Application
20220152214
The instant application contains a Sequence Listing that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The electronic copy of the Sequence Listing, created on Jan. 29, 2020, is named 024651_WO003_SL.txt and is 9,833 bytes in size.
Hematological malignancies comprise diseases resulting from transformation events occurring in immune or hematopoietic organs. Lymphoid malignancies arise from the accumulation of monoclonal neoplastic lymphocytes in lymph nodes and organs such as blood, bone marrow, spleen, and liver. Variants of these cancers comprise non-Hodgkin lymphomas (NHLs), including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), Richter transformation lymphoma (RTL), Burkitt lymphoma (BL), lymphoplasmacytoid lymphoma (LPL), Waldenström macroglobulinemia (WM), acute lymphocytic leukemia (ALL), and several types of T cell lymphomas. Acute myeloid leukemia (AML) results from the accumulation of neoplastic myeloid blasts in the bone marrow, blood, central nervous system, and other organs.
Depending partially upon the cell of origin (B cell or T cell), patients with NHL may experience disabling constitutional symptoms, lymphadenopathy and organomegaly that can induce life-threatening organ dysfunction, myelosuppression and immunocompromise that can result in susceptibility to infection and bleeding, and/or cutaneous manifestation that can be painful, intensely pruritic, and disfiguring. Patients with LPL/WM have an overproduction of immunoglobulin (Ig) M-producing plasma cells and can develop plasma hyperviscosity due to the presence of this circulating monoclonal IgM protein (M-protein). For patients with ALL or AML, disruption of normal bone marrow function by an expanding clone of leukemic blasts leaves them prone to life-threatening infection and bleeding.
Treatments for these diseases are intended to induce tumor regression, delay tumor progression, control disease-related complications, and extend life. Patients are commonly given chemotherapeutic and/or immunotherapeutic agents. Front-line therapies can provide durable remissions. However, many patients will eventually experience disease relapse; further sequential therapies are used to try to control disease manifestations. Despite use of agents with differing mechanisms of action, progressive tumor resistance often develops. Patients with multiple relapsed progressive disease have poor prognosis and are likely to die of their cancers. Thus, novel mechanisms of action are needed to safely offer new treatment options for patients with hematological cancers that have become resistant to existing therapies.
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a cell-surface protein that mediates signals from its ligand, the secreted glycoprotein Wnt5a. Consistent with its role in influencing the fate of stem cells during embryogenesis, ROR1 expression is observed on invasive malignancies that revert to an embryonic transcriptional program, but is not observed in normal adult tissues. ROR1 thus offers a favorable selectivity profile as a therapeutic target. ROR1 is commonly expressed on the malignant cells of patients with hematological cancers, and is also present on the cell surfaces of multiple solid tumors, where it appears to be a marker for cancer stem cells.
In view of the high unmet medical need in many patients with hematological and other cancers and the role of ROR1 in cancer, there is a need for new therapies that can improve outcomes for patients, including patients who do not respond to existing therapies, through targeting of ROR1.
The present invention relates to a method of treating a cancer patient using an immunoconjugate having the structure shown below.
wherein Ab is an antibody that specifically binds to human receptor tyrosine kinase like orphan receptor 1 (ROR1), wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NOs: 1 and 2, respectively; and wherein the immunoconjugate is administered to the patient at a dose of 0.25 to 4.00 mg/kg. As used herein, Formula I above is not intended to denote that each Ab may be conjugated to only one copy of the drug moiety shown in the formula. In some embodiments, the number or copy of the drug moiety per antibody (DAR) ranges from 1 to 7, where each drug moiety is conjugated to the antibody through a linker as shown in Formula I.
In some embodiments, the immunoconjugate is administered (e.g., intravenously) according to a dosage regimen described herein. The immunoconjugate may be administered, for example, at a dose of 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, or 3.00 mg/kg.
In certain embodiments, the immunoconjugate may be administered in repeated three-week cycles (e.g., on Day 1 or Days 1 and 8 per cycle). In certain embodiments, the immunoconjugate may be administered in repeated four-week cycles (e.g., on Days 1, 8, and 15 per cycle). In some embodiments, the number of cycles may total 3, 6, or more. In particular embodiments, the immunoconjugate may be administered: weekly for the first three, four, six, or eight weeks and then every three weeks; or every three weeks for the first three, six, or nine weeks and then weekly.
In some embodiments, the immunoconjugate is administered to a patient with a hematological cancer such as a lymphoid malignancy. In certain embodiments, the cancer is selected from the group consisting of CLL, SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL, WM, T cell NHL, ALL, and AML. In particular embodiments, the patient has been treated previously for the cancer, and/or has a cancer that is relapsed or refractory to treatment (e.g., one or more existing treatments for the cancer, such as all existing treatments).
In some embodiments, treatment with the immunoconjugate induces tumor regression (e.g., results in complete tumor eradication); delays tumor progression; inhibits cancer metastasis; prevents cancer recurrence or residual disease; decreases the size of nodal or extranodal tumor masses; decreases malignant cell numbers in bone marrow and peripheral blood; decreases malignant splenomegaly or hepatomegaly; improves cancer-related anemia, neutropenia, or thrombocytopenia; ameliorates cutaneous manifestation; decrease the likelihood of hyperviscosity syndrome in patients with LPL/WM; ameliorates disabling constitutional symptoms; and/or prolongs survival.
The present disclosure also provides an immunoconjugate for use in treating cancer in a patient in a method described herein. Further, the present disclosure provides the use of an immunoconjugate for the manufacture of a medicament for treating cancer in a patient in a method described herein.
The present invention provides treatment regimens using a ROR1 immunoconjugate. These treatment regimens may be used to treat a variety of cancers, such as those that are expected to express ROR1.
An “antibody-drug conjugate,” or “ADC,” or “immunoconjugate,” refers to an antibody molecule or an antigen-binding fragment thereof that is covalently or non-covalently bonded, with or without a linker, to one or more biologically active molecule(s). The present immunoconjugates comprise antibodies or fragments thereof that are specific for human ROR1 and thus can serve as excellent targeting moieties for delivering the conjugated payloads to cells (e.g., ROR1-positive cells). In certain embodiments, an immunoconjugate used in a treatment regimen of the invention is an immunoconjugate described in WO 2018/237335.
Shown below are SEQ ID NOs for the amino acid sequences of the heavy and light chain complementarity-determining regions (HCDRs and LCDRs), heavy and light chain variable domains (VH and VL), and heavy and light chains (HC and LC) of an exemplary anti-ROR1 antibody used in the immunoconjugates described herein:
In some embodiments, the antibody or antibody fragment in the immunoconjugate specifically binds human ROR1, and its heavy and light chains respectively comprise:
In certain embodiments of an immunoconjugate described herein, the antibody can be conjugated to the cytotoxic agent via a linker. In some embodiments, the linker is a cleavable linker. A cleavable linker refers to a linker that comprises a cleavable moiety and is typically susceptible to cleavage under in vivo conditions. In exemplary embodiments, the linker may comprise a dipeptide, such as a valine-citrulline (val-cit or VC) linker. In certain embodiments, the linker is attached to a cysteine residue on the antibody.
In some embodiments, the conjugation of the linker/payload to the antibody or fragment may be formed through reaction with a maleimide group (which may also be referred to as a maleimide spacer). In certain embodiments, the maleimide group is maleimidocaproyl (mc); thus, the linker/payload is conjugated to the antibody or fragment through reaction between a residue on the antibody or fragment and the me group in the linker precursor.
In some embodiments, the linker may include a benzoic acid or benzyloxy group, or a derivative thereof. In some embodiments, the linker includes a para-amino-benzyloxycarbonyl (PAB) group.
In some embodiments, the linkage between the Ab and payload or drug (D) components of the immunoconjugate may be formed through reaction of the components with a linker comprising a maleimide group, a peptide moiety, and/or a benzoic acid (e.g., PAB) group, in any combination. In certain embodiments, the maleimide group is maleimidocaproyl (mc). In certain embodiments, the peptide group is Val-Cit (VC). In certain embodiments, the linker comprises a Val-Cit-PAB group. In certain embodiments, the conjugation of the linker to the antibody or fragment may be formed from an mc-Val-Cit group. In certain embodiments, the linkage between the antibody or fragment and the drug moiety may be formed from an mc-Val-Cit-PAB group.
Linkers can be conjugated to the anti-ROR1 antibodies and antigen-binding fragments of the current disclosure in multiple ways. Generally, a linker and a cytotoxic moiety are synthesized and conjugated before attachment to an antibody. One method of attaching a linker-drug conjugate to an antibody involves reduction of solvent-exposed disulfides with dithiothreitol (DTT) or tris (2-carboxyethyl)phosphine (TCEP), followed by modification of the resulting thiols with maleimide-containing linker-drug moieties (e.g., 6-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-VC-PAB)). A native antibody contains 4 inter-chain disulfide bonds and 12 intra-chain disulfide bonds, as well as unpaired cysteines. Thus, antibodies modified in this way can comprise greater than one linker-drug moiety per antibody. In certain embodiments, the immunoconjugates each comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 linker/drug moieties. In certain embodiments, the immunoconjugates each comprise one or more (e.g., 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2) linker/drug moieties. In cases where the linker is branched and can each attach to multiple drug moieties, the ratio of the drug moiety to the antibody will be higher than using an unbranched linker.
In some embodiments, a suitable cytotoxic agent for use in an immunoconjugate described herein may be, e.g., an anti-tubulin agent such as an auristatin. In certain embodiments, the cytotoxic agent is monomethyl auristatin E (MMAE).
In some embodiments, an immunoconjugate described herein is constructed as follows:
The anti-ROR1 antibody may be an anti-ROR1 antibody described herein, e.g., an antibody with a heavy chain amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO: 2.
In particular embodiments, an immunoconjugate used in the treatment regimens of the invention has the following structure (I):
In some embodiments, the antibody is Ab1, which has a heavy chain amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO: 2 (Ab1); this immunoconjugate may have a DAR of 3-6 and is referred to herein as “ADC-A.” See also WO 2018/237335. The payload is conjugated to Ab1 through cysteine residue(s) in the antibody polypeptide chains.
In some embodiments, a ROR1 immunoconjugate described herein (e.g., ADC-A) is administered at a dose of 0.25 to 10 mg/kg, e.g., 0.25 to 4 mg/kg. For example, the immunoconjugate may be administered at a dose of 0.25 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 8, 9, or 10 mg/kg, or any combination thereof for multiple doses. In certain embodiments, the immunoconjugate is administered at a dose of 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, or 3.00 mg/kg.
In some embodiments, the immunoconjugate is administered in repeated cycles of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In certain embodiments, the immunoconjugate is administered in three-week cycles. In certain embodiments, the immunoconjugate is administered in four-week cycles. The treatment regimen may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more cycles of administration (e.g., 3 or more cycles, or 4 or more cycles). In certain embodiments, the immunoconjugate is administered on one, two, three, four, five, six, or seven days of the cycle. The days of administration may be consecutive or may have one, two, three, four, five, or six days, one week, two weeks, three weeks, or four weeks, or any combination thereof, between them. In particular embodiments, the immunoconjugate is administered on Day 1 only of each cycle (e.g., a three-week cycle). In particular embodiments, the immunoconjugate is administered on Days 1 and 8 of each cycle (e.g., a three-week cycle). In particular embodiments, the immunoconjugate is administered on Days 1, 8, and 15 of each cycle (e.g., a four-week cycle).
The immunoconjugate may be administered initially according to a dosage regimen described herein and subsequently according to a different dosage regimen described herein (e.g., to increase or decrease the frequency of administration). In some embodiments, the immunoconjugate is administered weekly during the first 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, then every 3 weeks thereafter. In certain embodiments, the immunoconjugate is administered weekly during the first 2, 3, 4, 5, or 6 weeks, and then every 3 weeks. In certain embodiments, the immunoconjugate is administered weekly during the first 1, 2, 3, 4, 5, or 6 weeks, and then every 4 weeks. The immunoconjugate may be administered, e.g.:
In some embodiments, a dosage regimen described herein achieves an immunoconjugate plasma Cmax of at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 μg/mL in the patient. In some embodiments, a dosage regimen described herein achieves an immunoconjugate plasma area under the concentration-time curve (AUC) of at least 500, 750, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, 3000, 3250, or 3500 hour·μg/mL in the patient.
In some embodiments, a dosage regimen described herein maintains immunoconjugate occupancy of the ROR1 receptor of at least 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% in the patient. In some embodiments, a dosage regimen described herein maintains at least 50% immunoconjugate occupancy of the ROR1 receptor for at least 20, 30, 40, 50, 60, 70, 80, or 90% of the time. In some embodiments, a dosage regimen described herein maintains at least 75% immunoconjugate occupancy of the ROR1 receptor for at least 20, 30, 40, 50, 60, 70, 80, or 90% of the time. In some embodiments, a dosage regimen described herein maintains at least 90% immunoconjugate occupancy of the ROR1 receptor for at least 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5% of the time.
The immunoconjugate may be administered via parenteral administration. As used herein, “parenteral administration” of an immunoconjugate includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the immunoconjugate through the breach in the tissue, thus generally resulting in the direct administration into the blood stream, into muscle, or into an internal organ. Parenteral administration thus includes, but is not limited to, administration of an immunoconjugate by injection of the immunoconjugate, by application of the immunoconjugate through a surgical incision, by application of the immunoconjugate through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intratumoral, and intrasynovial injection or infusions; and kidney dialytic infusion techniques. Regional perfusion is also contemplated. In some embodiments, the infusion may be administered by one route (e.g., intravenously) for initial doses and then be administered by another route for subsequent doses.
In certain embodiments, the immunoconjugate is administered by intravenous (IV) infusion. The IV infusion may take place over a period of about 0.1 to about 4 hours (e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 120, or 180). In particular embodiments, the infusion time is 30 minutes. Infusion times may be extended as necessary to accommodate individual patient tolerance of treatment. Where the immunoconjugate is administered in more than one dose, in some embodiments, the infusion time for the first dose is longer than the infusion time for subsequent doses, or alternatively, the infusion time for the first dose is shorter than the infusion time for subsequent doses.
In some embodiments, the immunoconjugate is administered as a monotherapy.
It is understood that the treatment regimens of the invention may be methods of treatment as described herein, an immunoconjugate as described herein for use in a treatment regimen described herein, or use of an immunoconjugate as described herein for the manufacture of a medicament for use in a treatment regimen described herein.
The treatment regimens of the invention may be used to treat a patient with cancer. In some embodiments, a treatment regimen of the invention includes the step of selecting a patient with a cancer described herein. In certain embodiments, the patient may have been treated previously for said cancer, and/or has a cancer that is relapsed or is refractory to one or more (or all) existing treatments for said cancer.
“Treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a biological disorder and/or at least one of its attendant symptoms. As used herein, to “alleviate” a disease, disorder or condition means reducing the severity and/or occurrence frequency of the symptoms of the disease, disorder, or condition. Further, references herein to “treatment” include references to curative, palliative and prophylactic treatment. Treatment of cancer encompasses inhibiting cancer growth (including causing partial or complete cancer regression), inhibiting cancer progression or metastasis, preventing cancer recurrence or residual disease, and/or prolonging the patient's survival.
In some embodiments, the patient to be treated with a treatment regimen of the invention has a ROR1-expressing cancer. The ROR1-expressing cancer can be determined by any suitable method of determining gene or protein expression, for example, by histology, flow cytometry, radiopharmaceutical methods, RT-PCR, or RNA-Seq. The cancer cells used for the determination may be obtained through tumor biopsy or through collection of circulating tumor cells. In certain embodiments, if an antibody-based assay such as flow cytometry or immunohistochemistry is used, ROR1-expressing cancers are any cancers with cells that show anti-ROR1 antibody reactivity greater than that of an isotype control antibody. In certain embodiments, if an RNA-based assay is used, ROR1-expressing cancers are those that show an elevated level of ROR1 RNA compared to a negative control cell or cancer that does not express ROR1.
In certain embodiments, the patient has a hematological malignancy, such as a lymphoid malignancy. In certain embodiments, the patient has a solid tumor. The patient may have a cancer selected from, e.g., lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), marginal cell B-cell lymphoma, Burkitt lymphoma (BL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), a non-Hodgkin lymphoma that has undergone Richter's transformation, T cell leukemia, T cell lymphoma (e.g., T cell non-Hodgkin lymphoma), lymphoplasmacytic lymphoma (LPL), Waldenström macroglobulinemia (WM), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), hairy cell leukemia (HCL), myeloma, multiple myeloma (MM), sarcoma (e.g., osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, soft-tissue sarcoma, or uterine sarcoma), brain cancer, glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, neuroblastoma, head and neck cancer, nasopharyngeal cancer, thyroid cancer, breast cancer (e.g., ER/PR-positive breast cancer, HER2-positive breast cancer, or triple-negative breast cancer), lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), malignant mesothelioma, bile duct/gall bladder cancer (e.g., cholangiocarcinoma), colon cancer, colorectal cancer, esophageal cancer, stomach cancer, gastric cancer, gastrointestinal stromal tumors (GIST), liver (hepatocellular) cancer, pancreatic cancer, renal cell carcinoma, bladder cancer, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer, testicular cancer, epithelial squamous cell cancer, melanoma, adrenocortical carcinoma, gastrointestinal carcinoid tumors, islet cell tumors, pancreatic neuroendocrine tumors, neuroendocrine carcinoma of the skin (Merkel cell carcinoma), and pheochromocytoma. In certain embodiments, the patient has a cancer that is refractory to other therapeutics (e.g., triple negative breast cancer).
In particular embodiments, the patient has a cancer selected from CLL/SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL/WM, T cell NHL, ALL, and AML. In certain embodiments, the patient may have been treated previously for said cancer, and/or has a cancer that is relapsed or is refractory to one or more (e.g., all) existing treatments for said cancer.
In some embodiments, the patient is resistant to or has relapsed on treatment with ibrutinib, acalabrutinib, autologous hematopoietic stem cell transplantation, bendamustine, bortezomib, brentuximab vedotin, carmustine, chimeric antigen receptor T (CAR-T) cells, cisplatin, copanlisib, cyclophosphamide, cytarabine, daratumumab, dexamethasone, doxorubicin, etoposide, gemcitabine, idelalisib, lenalidomide, melphalan, methotrexate, methylprednisolone, mosunetuzumab, obinutuzumab, ofatumumab, oxaliplatin, pinatuzumab, polatuzumab, rituximab, prednisone, radiotherapy, venetoclax, vincristine, or any combination thereof (e.g., any combination of prior treatment agents found in the Examples).
In some embodiments, the treatment regimen is administered to a human patient, e.g., an adult patient (≥18 years of age), an adolescent patient (≥12 to 17 years of age), or a pediatric patient (<18 years of age) with adequate performance status and organ function who (i) has a histologically confirmed advanced hematological cancer or solid tumor; and/or (ii) has a malignancy that is unlikely to be responsive to established therapies known to provide clinical benefit, or has developed an intolerance to established therapies known to provide clinical benefit. In certain embodiments, the patient meets both criteria.
In some embodiments, treatment with the immunoconjugate results in one or more of the following:
In some embodiments, a treatment regimen of the invention reduces tumor dimensions in a patient with a decrease of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in the sum of the products of the perpendicular diameters (SPD). In some embodiments, a treatment regimen of the invention reduces tumor dimensions in a patient with a decrease of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in the sum of the longest diameters of target lesions. In some embodiments, a treatment regimen of the invention completely eradicates the tumor.
In some embodiments, a treatment regimen of the invention (e.g., to treat CLL and/or SLL) results in one or more (e.g., any one, two, three, four, five, six, or seven) of the following.
In some embodiments, a treatment regimen of the invention (e.g., to treat CLL/SLL) results in one or more (e.g., any one, two, three, or four) of the following:
In some embodiments, a treatment regimen of the invention (e.g., to treat CLL/SLL) results in one or both of the following:
In some embodiments, a treatment regimen of the invention (e.g., to treat CLL/SLL) does not result in any of the following (which are signs of “progressive disease”):
In some embodiments, a treatment regimen of the invention (e.g., to treat lymphoma) results in one or more (e.g., any one, two, three, four, five, six, seven, or eight) of the following.
In some embodiments, a treatment regimen of the invention (e.g., to treat lymphoma) results in one or more (e.g., any one, two, three, or four) of the following:
In some embodiments, a treatment regimen of the invention (e.g., to treat lymphoma) results in one or more of the following:
a) no evidence of new disease;
b) no evidence of tumor growth; and
c) a <25% decrease and <25% increase from baseline in serum M-protein concentration (in subjects with LPL/WM).
In certain embodiments, a treatment regimen of the invention results in both a) and b) (“stable disease”) or a)-c) (“stable disease” in subjects with LPL/WM). In certain embodiments, a treatment regimen of the invention results in both a) and b) as well as a ≥25% but <50% decrease from baseline in serum M-protein concentration (“minor response” in LPL/WM).
In some embodiments, a treatment regimen of the invention does not result in one or more of the following (which are signs of “progressive disease”):
In some embodiments, a treatment regimen of the invention (e.g., to treat acute lymphoid leukemia) results in one or more (e.g., any one, two, or three) of the following:
In some embodiments, a treatment regimen of the invention (e.g., to treat acute lymphoid leukemia) results in one or more (e.g., any one, two, or three) of the following:
In certain embodiments, the treatment regimen results in all of a)-c) (“complete response with incomplete blood count recovery” and/or “complete response unconfirmed”).
In some embodiments, a treatment regimen of the invention (e.g., to treat acute lymphoid leukemia) results in one or more (e.g., any one, two, or three) of the following:
In certain embodiments, the treatment regimen results in all of a)-c) (“partial response”).
In some embodiments, a treatment regimen of the invention (e.g., to treat acute lymphoid leukemia) results in one or more (e.g., one, two, or three) of the following:
a) neither sufficient ALL improvement from baseline to qualify for PR nor sufficient evidence of ALL worsening to qualify for DRP;
b) no new or worsening extramedullary disease (including lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass, and no central nervous system involvement (e.g., CNS-1 status (no blasts in the cerebrospinal fluid) has not transitioned to CNS-2 status (WBC<5×109/L with presence of blasts in the cerebrospinal fluid) or to CNS-3 status (WBC≥5×109/L with presence of blasts in the cerebrospinal fluid) or to development of facial nerve palsy, brain/eye involvement, or hypothalamic syndrome));
c) no development of new mediastinal enlargement and no increase in the SPD of existing mediastinal enlargement by >25%.
In certain embodiments, a treatment regimen of the invention results in all of a)-c) (“stable disease”).
In some embodiments, a treatment regimen of the invention (e.g., to treat acute lymphoid leukemia) does not result in one or more (e.g., one, two, three, four, five, or six) of the following (which are signs of disease recurrence or progression, “DRP”):
In certain embodiments, the treatment does not result in any of a)-f).
In some embodiments, a treatment regimen of the invention (e.g., to treat acute myeloid leukemia) results in one or both of the following:
In some embodiments, a treatment regimen of the invention (e.g., to treat acute myeloid leukemia) results in one or both of the following:
In some embodiments, a treatment regimen of the invention (e.g., to treat acute myeloid leukemia) results in one or both of the following:
In some embodiments, a treatment regimen of the invention (e.g., to treat acute myeloid leukemia) results in one or both of the following:
In some embodiments, a treatment regimen of the invention (e.g., to treat acute myeloid leukemia) results in one or both of the following:
In some embodiments, a treatment regimen of the invention (e.g., to treat acute myeloid leukemia) does not result in one or more of the following (which are signs of disease recurrence or progression, “DRP”):
In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) results in one or both of the following:
a) disappearance of all target lesions and no new measurable lesions (e.g., lesions that can be accurately measured in ≥1 dimension (longest diameter to be recorded) as >10 mm with CT scan with minimum slice thickness of 5 mm) or >10 mm caliper measurement by clinical exam, or >20 mm by chest X-ray); and
b) reduction in the short axis to <10 mm for any pathological lymph nodes, whether target (e.g., ≥15 mm in short axis when assessed by CT scan (minimum slice thickness of 5 mm)) or nontarget (e.g., ≥10 mm but <15 mm).
In certain embodiments, the treatment regimen results in both a) and b) (“complete response” for target lesions).
In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) results in a ≥30% decrease in the sum of the diameters of target lesions taking as a reference the baseline sum of the diameters and including any new measurable lesions that may have appeared since baseline (“partial response” for target lesions).
In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) results in a ≥30% decrease in the sum of the diameters of target lesions taking as a reference the baseline sum of the diameters and including any new measurable lesions that may have appeared since baseline (“partial response” for target lesions).
In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) results in neither sufficient shrinkage to qualify for a partial response, taking as a reference the baseline sum of the diameters, nor sufficient increase to qualify for progressive disease, taking as a reference the smallest sum of the diameters during treatment (“stable disease” for target lesions).
In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) does not result in a ≥20% increase (and an absolute increase of ≥5 mm) in the sum of the diameters of the target lesions (including any new lesions), taking as a reference the smallest post-baseline sum (nadir tumor burden) or baseline sum if that is the smallest sum during treatment (“progressive disease” for target lesions).
In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) results in one or more of the following:
a) disappearance of all nontarget lesions;
b) normalization of an elevated tumor marker level; and
c) all lymph nodes nonpathologic in size (<10 mm in the short axis).
In certain embodiments, the treatment regimen results in all of a)-c) (“complete response” for nontarget lesions). In certain embodiments, the treatment regimen results in b) and c) but not a), or a) and c) but not b) (“non-complete response/non-progressive disease” for nontarget lesions).
In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) does not result in unequivocal progression of existing nontarget lesions (“progressive disease” for nontarget lesions”).
In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) results in an overall response of:
In some embodiments, a treatment regimen of the invention results in one or more of the following outcomes, e.g., as defined above or in the Examples:
In some embodiments, a treatment regimen of the invention does not result in one or more (e.g., any one, two, three, four, five, six, seven, eight, nine, or ten) of the following in the first cycle of treatment:
In some embodiments, a treatment regimen of the invention does not result in one or more (e.g., any one, two, three, four, five, or six) of the following:
In some embodiments, a treatment regimen of the invention does not result in one or more (e.g., any one, two, three, four, five, or six) of the following:
In some embodiments, a treatment regimen of the invention does not result in one or more (e.g., one, two, or three) of the following:
a) Grade ≥3 infusion reactions;
b) tumor lysis syndrome (TLS) of any grade; and
c) Grade ≥3 peripheral neuropathy;
wherein all grades are defined using the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.
In certain embodiments, a treatment regimen of the invention does not result in any of said outcomes.
In some embodiments, a treatment regimen of the invention does not result in abnormalities in one or more (e.g., any one, two, three, four, five, six, seven, eight, or nine) of the following: urine, serum, blood, systolic blood pressure, diastolic blood pressure, pulse, body temperature, blood oxygen saturation, and electrocardiography (ECG) readings. In certain embodiments, a treatment regimen of the invention does not result in abnormalities of any of the above.
In some embodiments, a treatment regimen of the invention does not result in detectable levels of circulating immunoconjugate-reactive antibodies in the patient's serum.
It is understood that the treatment regimens described herein may be methods of treatment as described herein, an immunoconjugate as described herein for use in a treatment regimen described herein, or use of an immunoconjugate as described herein for the manufacture of a medicament for a treatment regimen described herein.
In some embodiments, a patient to be treated with a treatment regimen of the invention is assessed for risk of tumor lysis syndrome (TLS) using the following criteria:
In some embodiments, if a patient is at intermediate or high risk of TLS, and/or if TLS is observed during treatment, the patient may receive allopurinol and/or febuxostat before or during treatment. A patient with hyperuricemia may additionally receive rasburicase. For example, the patient may receive said drug(s) according to a regimen described below:
(i) Intermediate Risk of TLS: The patient may receive allopurinol, 100 to 300 mg orally every 8 hours starting ≥24 to 48 hours before the start of drug therapy; of note, the maximum daily allopurinol dose is 800 mg, doses ≤300 mg need not be divided, and doses should be reduced by ≥50% in subjects with renal insufficiency. Alternative drugs (eg, febuxostat) may be substituted, with administration per product labelling. In addition, patients with hyperuricemia may receive rasburicase, 3 to 4.5 mg by IV infusion.
(ii) High Risk of TLS: The patient may receive allopurinol, 100 to 300 mg orally every 8 hours starting ≥24 to 48 hours before the start of drug therapy; of note, the maximum daily allopurinol dose is 800 mg, doses ≤300 mg need not be divided (but may be insufficient for high-risk subjects), and doses should be reduced by 50% in subjects with renal insufficiency. Alternative drugs (eg, febuxostat) may be substituted, with administration per product labelling. In addition, high risk patients may receive rasburicase, 3 to 4.5 mg by IV infusion, administered 3 to 4 hours prior to the first dose of drug.
In some embodiments, patients are monitored for TLS during Cycle 1, Day 1 (C1D1) through C1D3 with assessments of vital signs, AEs, and serum chemistry and hematology laboratory studies.
In some embodiments, before or while receiving a treatment regimen of the invention, a patient may receive an antipyretic and/or an antihistamine to reduce the incidence and severity of infusion reactions. In certain embodiments, the antipyretic may be administered by the oral or IV route, and may be, e.g., acetaminophen (paracetamol), 650 to 1,000 mg or equivalent. In certain embodiments, the antihistamine may be administered by the oral or IV route, and may be, e.g., cetirizine, 10 mg or equivalent. In some embodiments, one or both drugs are given 30 to 60 minutes prior to each immunoconjugate infusion. A nonsteroidal antiinflammatory drug (NSAID) such as ibuprofen, 400 to 800 mg orally or equivalent, may be added or substituted for acetaminophen. A corticosteroid such as prednisolone, 100 mg or equivalent, may also be considered as a premedication.
In some embodiments, before or while receiving a treatment regimen of the invention, a patient may receive an antiemetic to treat nausea and/or vomiting.
Neutropenia Management
In some embodiments, before or while receiving a treatment regimen of the invention, a patient may receive G-CSF (e.g., filgrastim, frastim-SND, PEG-filgrastim, or lenograstim) or GM-CSF (e.g., sargramostim) to prevent or mitigate drug-induced neutropenic complications and promote neutrophil recovery.
HVS is a clinical feature in 10% to 30% of patients with LPL/WM due to the presence of high levels of circulating M-protein. Immediate therapy of symptomatic HVS is typically plasmapheresis. In some embodiments, before or while receiving a treatment regimen of the invention, a patient may receive plasmapheresis to prevent or mitigate HVS.
The present invention also provides articles of manufacture, e.g., kits, comprising one or more containers (e.g., single-use or multi-use containers) containing a pharmaceutical composition of an immunoconjugate described herein at a dose described herein, optionally an additional biologically active molecule (e.g., another therapeutic agent), and instructions for use according to a treatment regimen described herein. The immunoconjugate and additional biologically active molecule can be packaged together or separately in suitable packing such as a vial or ampule made from non-reactive glass or plastic. In some embodiments, the vial or ampule holds a liquid containing the immunoconjugate or a lyophilized powder comprising the immunoconjugate; the liquid or lyophilized powder may optionally include the additional therapeutic agent or biologically active molecule. In certain embodiments, the vial or ampule holds a concentrated stock (e.g., 2×, 5×, 10× or more) of the immunoconjugate and optionally the biologically active molecule. In particular embodiments, a pharmaceutical composition of an immunoconjugate described herein (e.g., ADC-A) is packaged in a single-use glass vial containing 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg of the immunoconjugate (e.g., appropriate for use at a dose described herein, such as 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, or 3.00 mg/kg). In certain embodiments, the articles of manufacture such as kits include a medical device for administering the immunoconjugate and/or biologically active molecule (e.g., a syringe and a needle); and/or an appropriate diluent (e.g., sterile water and normal saline). The present invention also includes methods for manufacturing said articles.
Unless the context requires otherwise, throughout the specification and claims, the word “comprise” and variations thereof, such as, “comprises” and “comprising,” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise. As used herein the term “about” refers to a numerical range that is 10%, 5%, or 1% plus or minus from a stated numerical value within the context of the particular usage. Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed embodiments.
All publications and patents mentioned herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the constructs and methodologies that are described in the publications, which might be used in connection with the presently described inventions. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors of the subject invention are not entitled to antedate such disclosure by virtue of prior invention or for any other reason.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the inventions described herein belong. Any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the inventions described herein.
The following examples illustrate representative embodiments of the present invention and are not meant to be limiting in any way.
Conjugation of Ab1 with MC-VC-PAB-MMAE (ADC-A) was performed at multiple scales (from 2 mg to 200 g) with similar results. At a large scale, approximately 200 g of Ab1 (approximately 40 mg/mL in 50 mM sodium citrate, 10 mg/mL trehalose, 0.05 mM EDTA, 0.02% polysorbate 80, pH 5.2) was treated with 1.90 equivalents (eq) of tris(2-carboxyethyl)phosphine (TCEP, 5 mM) and held at 20-24° C. for 330 minutes. Next, 6.5 eq MC-VC-PAB-MMAE in N,N-dimethylacetamide (DMA) was added and the mixture was held at 22-23° C. for an additional 60 minutes. The buffer was exchanged with 10 mM sodium acetate, pH 4.8 by ultrafiltration/diafiltration (UF/DF) using 30 kD UF membrane cassettes. The number of MMAE drug molecules linked per antibody molecule (DAR) was determined using HIC-HPLC. Data from HIC-HPLC, SEC-HPLC, RP-HPLC, and UV/Vis are summarized in Table 1 below. Consistent results were obtained at all scales, with DAR ranging from 3.89 to 5.09 on average, depending on the methodology used.
The following describes a protocol for evaluating the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy of a ROR1 immunoconjugate (ADC-A) across a range of dose levels when administered to subjects with previously treated relapsed or refractory CLL/SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL/WM, T cell NHL, ALL, or AML. ADC-A is administered intravenously (IV) in repeated 3-week cycles with a drug infusion on Day 1 of each cycle (Q1/3W [Schedule 1]); in repeated 3-week cycles with drug infusions on Days 1 and 8 of each cycle (Q2/3W [Schedule 2]); or in repeated 4-week cycles with drug infusions on Days 1, 8, and 15 of each cycle (Q3/4W [Schedule 3]) over a planned infusion time of ˜30 minutes. Infusion times may be extended as necessary to accommodate individual subject tolerance of treatment.
The initial cohort of subjects will be prescribed ADC-A at 0.50 mg/kg Q1/3W. Thereafter, cohorts of subjects will be sequentially enrolled at progressively higher starting dose levels of ADC-A to be administered Q1/3W, Q2/3W, or Q3/4W (Tables 2 and 3). An initial dose of 0.25 mg/kg may be administered in the Q1/3W schedule to permit a dose decrement if a subject experiences a TEAE requiring dose modifications to a level below the starting level.
§May be administered if subjects tolerate ADC-A therapy at the prior dose level.
An accelerated dose escalation in a single subject at the initial dose level using the Q1/3W schedule is planned. Thereafter, cohorts of 3 to 6 subjects will be sequentially enrolled evaluating each schedule of administration at progressively higher dose levels of ADC-A using a standard 3+3 dose-escalation design. Based on the pattern of dose-limiting toxicities (DTLs) observed in Cycle 1, escalation will proceed to define a maximum-tolerated dose (MTD) and a recommended dosing regimen (RDR) for each schedule of administration that may be at the MTD or a lower dose within the tolerable dose range. The MTD is the highest tested dose level at which ≥6 subjects have been treated and which is associated with a Cycle 1 dose-limiting toxicity (DLT) in ≤17% of the subjects. The RDR may be the MTD or may be a lower dose within the tolerable dose range. Selection of each RDR will be based on consideration of short- and long-term safety information together with available pharmacokinetic, pharmacodynamic, and efficacy data, and may be defined in the context of the level of supportive care (eg, antiemetic or hematopoietic prophylaxis) provided to subjects to achieve the RDR. Once each RDR has been established, further development will be considered in specific hematological cancers and/or solid tumors.
It is expected that ADC-A administered to the patients in accordance with the dosing regimens provided will achieve overall response (OR), defined as achievement of the following outcomes by disease type:
CR without measurable residual disease (CRMRD−) is defined as the achievement of ≤1×10−4 malignant cells in bone marrow (as assessed by flow cytometry) in a subject who meets all other criteria for CR. It is also expected that ADC-A when provided in accordance with the dosing regimens provided herein will lead to improvements in percent change in tumor dimensions (defined as the percent change from baseline in the sum of the products of the diameters (SPD) of index lesions), progression-free survival (PFS) (defined as the interval from the start of study therapy to the earlier of the first documentation of disease progression/relapse or death from any cause), and overall survival (OS) (defined as the interval from the start of study therapy to death from any cause).
The ADC-A dosing regimen may also lead to changes (e.g., increase or decrease) in plasma concentrations of Wnt5a (as assessed by immunoassay), changes (e.g., increase or decrease) in plasma concentrations of circulating ROR1 (as assessed by immunoassay), and alteration in the numbers (e.g., increase or decrease) or activation status (e.g., increase or decrease) of immune cells such as circulating B cells, T cells and natural killer (NK) cells.
In the study, the patients may be adult patients who are 18 years or older; have been diagnosed with CLL/SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL/WM, T cell NHL, ALL, or AML; have been previously treated but have progressed during or relapsed after prior systemic therapy, or are unlikely responsive to established therapies known to provide clinical benefit or have developed an intolerance to established therapies known to provide clinical benefit; and have completed all previous therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of cancer ≥1 week before the start of study therapy.
Patients who have ongoing immunosuppressive therapy other than corticosteroids may be excluded from the treatment. At the time of starting study therapy, subjects may be using systemic corticosteroids (at doses of ≤10 mg/day of prednisone or equivalent), or topical, inhaled, or intra-articular corticosteroids. During study therapy, subjects may use systemic, enteric, topical, inhaled, or intra-articular corticosteroids, as required (e.g., for intercurrent medical conditions or antiemetic prophylaxis).
To prevent tumor lysis syndrome (TLS), the patients may be given allopurinol, 100 to 300 mg orally every 8 hours starting ≥24 to 48 hours before the start of study drug therapy. Alternative drugs (e.g., febuxostat) may be substituted, with administration per product labelling. In addition, subjects with hyperuricemia may receive rasburicase, 3 to 4.5 mg by IV infusion. In addition, high-risk subjects may receive rasburicase, 3 to 4.5 mg by IV infusion, administered 3 to 4 hours prior to the first dose of study drug.
If infusion reactions are observed, subjects may be premedicated before ADC-A infusions with an antipyretic and an antihistamine to reduce the incidence and severity of infusion reactions. The regimen may be an oral or IV antipyretic (acetaminophen [paracetamol], 650 to 1,000 mg or equivalent) and an oral or IV antihistamine (cetirizine, 10 mg or equivalent) both given 30 to 60 minutes prior to each ADC-A infusion. A nonsteroidal antiinflammatory drug (NSAID) (ibuprofen, 400 to 800 mg orally or equivalent) may be added or substituted for acetaminophen. A corticosteroid (100 mg of prednisolone or equivalent) as a premedication can be considered, as needed.
Responses will be categorized as complete response without measurable residual disease (CRMRD−), complete response (CR), complete response with incomplete blood count recovery (CRi), partial response (PR), partial response with lymphocytosis (PR-L), stable disease (SD), or progressive disease (PD). In addition, a response category of nonevaluable (NE) is provided for situations in which there is inadequate information to otherwise categorize response status.
The best overall response will be determined. The best overall response is the best response recorded from the start of treatment until PD/recurrence. The screening measurement will be taken as a reference for determinations of response. The nadir measurement will be taken as a reference for PD; this measurement constitutes the smallest measurement recorded, including the screening measurement if this is the smallest measurement. Where imaging data are available, these data will supersede physical examination data in determining tumor status.
(1) Complete Response without Measurable Residual Disease
To satisfy criteria for CRMRD−, all of the following conditions must be attained:
To satisfy criteria for CR, all of the following conditions must be attained:
To satisfy criteria for a PR, all of the following conditions must be attained:
To satisfy criteria for SD, the following conditions must be attained:
The occurrence of any of the following events indicates definitive PD:
Responses will be categorized as complete response without measurable residual disease (CRMRD−), complete response (CR), very good partial responses (VGPR; LPL/WM only), partial response (PR), minor response (MR; LPL/WM only), stable disease (SD), or progressive disease (PD). In addition, a response category of nonevaluable (NE) is provided for situations in which there is inadequate information to otherwise categorize response status.
The best overall response will be determined. The best overall response is the best on-treatment response from screening recorded from the start of treatment until PD/recurrence. The screening measurement will be taken as a reference for determinations of response. The nadir measurement will be taken as a reference for PD; this measurement constitutes the smallest measurement recorded, including the screening measurement if this is the smallest measurement. For FDG-avid tumors, metabolic criteria for response by PET-CT will take precedence over anatomic criteria for response by contrast CT when assessing CR.
(1) Complete Response without Measurable Residual Disease
To satisfy criteria for CRMRD−, all of the following conditions must be attained:
To satisfy criteria for CR, all of the following conditions must be attained:
To satisfy criteria for PR, all of the following conditions must be attained:
To satisfy criteria for MR, all of the following conditions must be attained:
To satisfy criteria for SD, all of the following conditions must be attained:
The occurrence of any of the following events indicates PD:
Responses will be categorized as complete response without measurable residual disease (CRMRD−), complete response (CR), complete response with incomplete blood count recovery (CRi) (including also unconfirmed complete response [CRu] for subjects with mediastinal disease), partial response (PR), stable disease (SD), treatment failure (TF) or disease recurrence or progression (DRP). In addition, a response category of nonevaluable (NE) is provided for situations in which there is inadequate information to otherwise categorize response status.
The best overall response will be determined. The best overall response is the best on-treatment response from baseline recorded from the start of treatment until DRP. The baseline measurement will be taken as a reference for determinations of response. The nadir measurement will be taken as a reference for DRP; the best on-study measurement constitutes the measurement with the least tumor involvement, including the baseline measurement if this is the measurement meeting this criterion.
(1) Complete Response without Measurable Residual Disease
To satisfy criteria for CRMRD−, all of the following conditions must be attained:
To satisfy criteria for CR, all of the following conditions must be attained:
To satisfy criteria for PR, all of the following conditions must be attained:
To satisfy criteria for SD, all of the following conditions must be attained:
The occurrence of any of the following events indicates DRP:
Responses will be categorized as complete response without measurable residual disease (CRMRD−), complete response (CR), complete response with incomplete blood count recovery (CRi), morphologic leukemia-free state (MLFS), partial response (PR), stable disease (SD), treatment failure (TF), or disease recurrence or progression (DRP). In addition, a response category of nonevaluable (NE) is provided for situations in which there is inadequate information to otherwise categorize response status.
The best overall response will be determined. The best overall response is the best on-treatment response from baseline recorded from the start of treatment until DRP or TF. The baseline status will be taken as a reference for determinations of response. The best on-study measurement will be taken as a reference for DRP; the best on-study measurement constitutes the measurement with the least tumor involvement, including the baseline measurement if this is the measurement meeting this criterion.
(1) Complete Response without Measurable Residual Disease
To satisfy criteria for CRMRD−, all of the following conditions must be attained:
To satisfy criteria for CR, all of the following conditions must be attained:
To satisfy criteria for MLFS, all of the following conditions must be attained:
To satisfy criteria for PR, all of the following conditions must be attained:
To satisfy criteria for SD, all of the following conditions must be attained:
The occurrence of any of the following events indicates DRP:
Samples to be obtained and parameters to be analyzed are indicated in Table 4.
Grading of adverse event severity, as applied herein, is described in Table 5 below.
Data have been obtained from 25 subjects with hematological malignancies, including 12 subjects with MCL, 7 subjects with CLL/SLL, 2 subjects with DLBCL, 2 h subjects with FL, 1 subject with MZL, and 1 subject with RTL. Subjects were heavily pretreated with a median (range) of 4 (1-23) prior systemic chemotherapy regimens, including hematopoietic stem cell transplantation (HSCT) in 4 subjects and chimeric antigen receptor (CAR)-T-cell or natural killer (NK) therapy in 3 subjects.
96 doses of ADC-A were administered, including 1 at the 0.5 mg/kg dose level, 9 at the 1.0 mg/kg dose level, 18 at the 1.5 mg/kg dose level, 46 at the 2.25 mg/kg dose level, and 22 at the 2.5 mg/kg dose level. The number of cycles of therapy received ranged from 1 to 10. All subjects received ADC-A on the Q1/3W schedule of administration (Table 2).
Treatment with ADC-A was generally well-tolerated, with neutropenia being the primary acute toxicity. No DLTs were observed at doses of 0.5, 1.0, and 1.5 mg/kg. A DLT of Grade 4 neutropenia in C1 was noted in 1 of 7 subjects at ADC-A 2.25 mg/kg. In addition, 1 subject receiving ADC-A 2.25 mg/kg experienced Grade 3 neutropenia in C1, and 1 subject receiving ADC-A 2.25 mg/kg experienced Grade 4 neutropenia in C2. In each of these 3 cases, neutropenia was observed on approximately Day 15 of the cycle. Neutropenia was responsive to granulocyte colony-stimulating factor (G-CSF) given reactively or as secondary prophylaxis. No neutropenic fever or infection occurred. A subject starting at ADC-A 2.5 mg/kg experienced Grade 4 thrombocytopenia in C1; however, this subject had a history of thrombocytopenia, including Grade 2 thrombocytopenia at baseline, her post-baseline platelet abnormalities were not clearly drug related, and she continued with C2 and C3 therapy at ADC-A 2.5 mg/kg.
One subject had Grade 2 neuropathy following administration of 5 cycles of ADC-A 2.25 mg/kg; treatment was delayed for 1 cycle and therapy was resumed at a dose of 1.5 mg/kg. Other adverse events, laboratory abnormalities, and ECG findings were low-grade, did not appear to be dose- or exposure-dependent, and likely had resulted from the underlying cancer, comorbid conditions, intercurrent illnesses, or concomitant medications. No infusion reactions or tumor lysis syndrome were observed.
Plasma concentrations of total ADC-A and MMAE over time for 16 patients dosed with ADC-A are shown in
Increases in Cmax and AUC for were generally dose-proportional for ADC-A and somewhat less than dose-proportional for MMAE. Mean tin values for ADC-A ranged from 2.1 to 3.0 days, independent of the dose administered.
Pharmacodynamic data from subjects with CLL have shown concentration- and time-dependent ADC-A occupancy of ROR1 receptors in circulating CLL cells (
The correlation of unoccupied ROR1 receptors with ADC-A plasma concentrations, as shown in
Pharmacokinetic simulations were run to further explore potential ADC-A dosing regimens. The simulations indicate that weekly administration of ADC-A may be more effective than administration once every three weeks (
Antitumor activity was observed in heavily pretreated subjects with MCL (including three partial responses) and DLBCL (including one partial response) (
One subject with MCL displayed extensive preexisting disease, with lesions in the palate, neck, chest, abdomen, and pelvis. The subject had received heavy prior therapy with R-hyper-CVAD with R/methotrexate/cytarabine, rituximab, ibrutinib, daratumumab, lenalidomide-rituximab, and radiotherapy. The subject showed evidence of an objective tumor response to treatment with 2.25 mg/kg of ADC-A over three cycles. All measured nodal groups showed reductions in tumor dimensions, with a 53% decrease in SPD (sum of the products of the perpendicular diameters). Further, a palate lesion also decreased in size and tissue infiltration. The magnitude of the response appears to qualify as a partial response (PR). The subject did not display signs of any drug-related hematologic or nonhematologic toxicity.
Another subject with MCL displayed both a palate mass and extranodal disease, and had received heavy prior therapy with rituximab, rituximab/bortezomib, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), BR (bendamustine and rituximab, R-hyper-CVAD with intrathecal prophylaxis, ibrutinib, and mosunetuzumab. The subject showed evidence of an objective tumor response to treatment with 2.5 mg/kg of ADC-A over three cycles. The subject reported that his activity had increased and fatigue had largely resolved; further, the palate lesion decreased in size by 85%. The magnitude of the response appears to qualify as a partial response (PR).
Another subject with MCL displayed orbit lesions and extranodal disease, and had received heavy prior therapy with R-CHOP, rituximab, ibrutinib-rituximab, and rituximab-BEAM (carmustine, cytarabine, etoposide, and melphalan). The subject showed evidence of an objective tumor response to treatment with 2.5 mg/kg of ADC-A over six cycles, with a 51% decrease in SPD for tumor lesions. The magnitude of the response appears to qualify as a partial response (PR).
One subject with DLBCL displayed extranodal disease, and had received heavy prior therapy with R-CHOP, R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine, and cisplatin), R-GEMOX (rituximab, gemcitabine, and oxaliplatin), BEAM plus autologous transplant, pinatuzumab-rituximab, bendamustine-rituximab, and CAR-T cells with fludarabine conditioning. The subject showed evidence of an objective tumor response to treatment with ADC-A over six cycles (2.25 mg/kg in Cycle 1, a reduced dose in Cycle 2, 2.25 mg/kg in Cycles 3-5, and 2.5 mg/kg in Cycles 6 and 7). Both measured nodal groups showed reductions in tumor dimensions, with a 68% decrease in SPD. The magnitude of the response appears to qualify as a partial response (PR).
While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.
The amino acid sequences described herein are listed in Table 8 below.
This application claims priority from U.S. Provisional Patent Application 62/800,187, filed Feb. 1, 2019, whose disclosure is incorporated by reference herein in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2020/016301 | 2/1/2020 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62800187 | Feb 2019 | US |
