Patent Application
20210346520
This disclosure relates generally to methods of treating cancer. More specifically, this disclosure relates to treatment of tumors in a patient with advanced pancreatic adenocarcinoma by administering a tumor-targeted vector encoding a dominant-negative cyclin G1 inhibitor.
Pancreatic adenocarcinoma (PDAC) is projected to become the second leading cause of cancer death in the US and is rising worldwide1,2. For patients with advanced disease, first3,4 and second line5 treatment options may improve survival modestly but are not curative. Unfortunately, there have been few successful targeted therapy options6 in part because the most common mutations (KRAS, TP53) have not been targetable, and others are uncommon (BRCA1, BRCA2, and MSI). As with most cancers, genetic dysfunction of the normal cell division cycle and its checkpoint control elements may be critical to progression of PDAC7; therefore, targeting the executive elements of cell cycle checkpoint control may represent a promising strategy8.
DeltaRex-G (Former names: Mx-dnG1, Rexin-G) is the first targeted injectable vector to be approved for clinical trials in the treatment of metastatic cancers9. DeltaRex-G (
Based on encouraging clinical data from the Philippines in patients with metastatic PDAC15-16, clinical trials began in the United States using DeltaRex-G for standard chemotherapy-resistant PDAC, sarcoma, osteosarcoma, and breast cancer17-19. In this disclosure, we provide results, along with new mechanistic and pharmacological insights, from an advanced Phase I/II study evaluating over-all safety and potential antitumor activity of intravenous infusions of DeltaRex-G in metastatic gemcitabine-resistant PDAC.
Other viral gene therapy approaches for pancreatic adenocarcinoma include an on-going Phase 1 trial combining oncolytic adenovirus-mediated cytotoxic and IL-12 gene therapy with chemotherapy in metastatic PDAC (www.clinicaltrials.gov), and a recently completed Phase III randomized controlled clinical trial of PANVAC-VF for the treatment of patients with advanced pancreatic cancer. PANVAC™-VF is a vaccine regimen composed of a priming dose of recombinant vaccinia virus and booster doses of recombinant fowl pox virus expressing carcinoembryonic antigen, mucin-1 and a triad of costimulatory molecules (TRICOM), given subcutaneously, followed by injection of recombinant granulocyte-macrophage colony-stimulating factor at the vaccination site31-32. However, the Phase III randomized trial did not meet it primary endpoint of improving overall survival when compared with physician's choice of palliative therapy33. Both viral gene therapies for PDAC involve either intratumor or subcutaneous viral vector injections. In contrast, DeltaRex-G involves a systemically (intravenously) administered tumor-targeted gene delivery approach (
DeltaRex-G is a potent inhibitor of the human Cyclin G1 Pathway (CCNG1 proto-oncogene). CCNG1 gene expression plays a powerful executive role in cell cycle regulation, exerting significant influence on critical oncogenic drivers: including the potent Mdm2 and cMyc oncoproteins, and the p53 tumor suppressor protein, gatekeeper of DNA fidelity34. CCNG1 is overexpressed in over 50% of various malignancies: including pancreatic, breast, prostate, ovarian, and colon cancer35. Albeit a small study in patient number, the single-agent antitumor activity of DeltaRex-G in metastatic pancreatic adenocarcinoma is evident. In addition to the single agent efficacy observed in the oncology clinic, molecular mechanisms were histologically revealed: as repeated intravenous infusion on DeltaRex-G induced apoptosis of cancer cells, stromal fibroblasts and associated tumor vasculature in biopsied tumors of DeltaRex-G treated patients19,36,37. Conceivably, patients whose tumors overexpress CCNG1, revealing a pathological distortion in growth control pathways, will respond favorably to Cyclin G1 inhibitor therapy, delivered precisely. Without being bound by any particular theory, the DeltaRex-G induced tumor eradication by enforced apoptosis of cancer cells that was observed histologically, as well as supportive neo-vasculature and associated/malignant fibroblasts of the TME, is the executive mechanism of DeltaRex-G anticancer activity. Moreover, the demonstrated eradication of refractory chemo-resistant pancreatic cancer (that is, progressive eradication upon continued intravenous infusions) is certainly noteworthy and potentially important—prompting us to closely examine the anaplastic Signature (Sig) proteins with an aim toward “further optimizing” these pioneering aspects of tumor-targeted gene delivery in future investigations44.
The present disclosure provides methods for treating a patient having advanced metastatic cancer, wherein the patient has failed at least one treatment regimen for the advanced metastatic cancer. In some embodiments, the patient has failed at least two treatment regimens. In certain embodiments, at least one treatment regimen comprised administration of gemcitabine. As a result, one or more tumors are resistant to gemcitabine or are otherwise resistant to certain first and/or second line therapeutic options. The methods comprise administering a plurality of intravenous infusions of a vector comprising a tumor signature-targeting peptide and a nucleic acid that encodes a dominant negative human cyclin G1 construct The vector may be DeltaRex-G.
The words “treating” and “treatment” have their usual meanings in medical science, that is, “treating” means the management and care of a patient to cure or alleviate a disease or disorder or one or more of the symptoms thereof. A treatment may achieve a “cure,” that is, a complete and permanent remission of a cancer, but it need not be a cure. Treatment may be undertaken to alleviate symptoms, for example, to decrease tumor size, the number and location of metastases, or the physiological effects of tumor burden. Treatment may lead to temporary remission or render the tumor more amenable to other therapeutic options (such as surgery, radiation, or treatment with a different therapeutic agent or combination of agents). It should also be noted that use of the terms “treating” and “treatment” is not meant to exclude other actions that may be necessary or desirable for the management and care of a cancer patient but that are not recited in the methods described in this disclosure, e.g., use of IV fluids for the patient's hydration or use of medications to treat pain.
In some embodiments, the vector may be administered in a 6-week cycle encompassing 4 weeks of treatment followed by 2 weeks of rest. The vector may be administered once weekly during the treatment weeks, twice weekly, or more frequently. Depending on the cancer's response and patient tolerance, the vector may be administered from between one cycle and thirteen cycles. In certain embodiments, the vector may be administered from between five cycles and thirteen cycles
In some embodiments, the vector dose may be between about 1×1011 to about 500×1011 colony forming units (cfu). In certain embodiments, the therapeutically effective dose is about 1×1011 cfu, 5×1011 cfu, 9×1011 cfu, 22×1011 cfu, 24×1011 cfu, 30×1011 cfu, 49×1011 cfu, 60×1011 cfu, 156×1011 cfu, 314×1011 cfu, or 453×1011 cfu.
In some embodiments, the patient may have metastatic pancreatic adenocarcinoma. The patient may have at least one lesion in the pancreas, liver, lymph nodes, lung, trachea, adrenal glands, mesentery, bone, or omentum. In other embodiments, the patient may further display malignant ascites, pleural effusion, and/or peritoneal carcinomatosis.
In some embodiments, the patient may be administered one or more additional therapeutic agents, for example, an immune-modulatory monoclonal antibody, a cytotoxic chemotherapy, an anti-angiogenesis agent, a selective tyrosine kinase inhibitor, or a monoclonal antibody directed against specific features of cells from the metastatic cancer. In certain embodiments, the additional therapeutic agent comprises an immune-modulatory monoclonal antibody. In a subset of such embodiments, the therapeutic agent may be one or more checkpoint inhibitors. In certain other embodiments, the additional therapeutic agent comprises a cytotoxic chemotherapy agent. In a subset of such embodiments, the therapeutic agent may be doxorubicin, trabectedin, other known chemotherapy agent, or combination thereof. In certain other embodiments, the additional therapeutic agent comprises an anti-angiogenesis agent. In a subset of such embodiments, the therapeutic agent may be bevacizumab. In certain other embodiments, the additional therapeutic agent comprises a selective tyrosine kinase inhibitor. In certain other embodiments, the additional therapeutic agent comprises one or more monoclonal antibodies directed against specific features of cells from the metastatic cancer. In a subset of such embodiments, the therapeutic agent may be panitumumab, cetuximab, or a combination thereof.
It will be readily understood that the embodiments, as generally described herein, are exemplary. This detailed description of various embodiments is not intended to limit the scope of the present disclosure but is merely representative of various embodiments.
The following examples are for illustration only. In light of this disclosure, those of skill in the art will recognize that variations of these examples and other embodiments of the disclosed subject matter are enabled without undue experimentation.
DeltaRex-G (
Detection of anti-vector antibodies in serum, testing for presence of replication competent retrovirus and vector DNA integration studies in patient peripheral blood lymphocytes, were performed as described previously17.
This was an open label, single aim, dose-seeking study that incorporated a modification of the standard Cohort of 3 design, that allowed patients to continue the study drug into Phase II18-19. Treatment with DeltaRex-G comprised 6-week cycles that encompassed 4 weeks of treatment, followed by 2 weeks of rest. Four dose levels were given, beginning at 1.0×1011 cfu given by intravenous (i.v.) infusion two times per week. Three patients were to be treated at each dose level with expansion to 6 patients per cohort if dose-limiting toxicity (DLT) was observed in any 1 of the first 3 patients at each dose level. The maximum tolerated dose (MTD) was defined as the highest dose in which 0 of 3 or ≤1 of 6 patients experienced a DLT, with the next higher dose level having at least 2 patients who experienced a DLT. A DLT was defined as any National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) Grade 3, 4, or 5 adverse event (AE) considered possibly, probably, or definitely related to the study drug, excluding the following: Grade 3 absolute neutrophil count lasting<72 hours: Grade 3 alopecia; or any Grade 3 or higher incident of nausea, vomiting, or diarrhea in a patient who did not receive maximal supportive care39.
For the Phase II part of the study, patients who had no toxicity or in whom toxicity had resolved to Grade 1 or less could receive additional cycles of therapy. Protocol Amendments I and II permitted an intra-patient dose escalation up to Dose Level II for patients who had no toxicity or in whom toxicity had resolved to Grade 1 or less, once safety had been established at the higher dose level in a simultaneously conducted Phase I/II study for sarcoma18. Additionally, each cohort also could be expanded to 6 or 7 patients if significant biologic activity (stable disease or better) was noted at each dose level. The principal investigator was allowed to recommend surgical resection/debulking after at least one treatment cycle has been completed. Response was evaluated first using the Response Evaluation Criteria in Solid Tumors40. Additional evaluations used the International Positron Emission Tomography (PET) criteria41 and a modified RECIST as described by Choi et al.42. Safety and efficacy analyses were conducted by the site Principal Investigators.
Inclusion Criteria: Candidates included in the study had to have a histologically or cytologically confirmed pathologic diagnosis of advanced or metastatic pancreatic adenocarcinoma that was resistant to gemcitabine or a gemcitabine—containing regimen, be ≥18 years of age, have an Eastern Cooperative Oncology Group (ECOG) performance score of 0-1, and acceptable hematologic, hepatic, and kidney function.
Exclusion criteria included human immunodeficiency vims, hepatitis B virus, or hepatitis C virus positivity, clinically significant ascites, medical or psychiatric conditions that could compromise proper adherence to the protocol, and unwillingness to employ effective contraception during treatment with DeltaRex-G and for 6 weeks following treatment completion.
The clinical protocol was reviewed and approved by the Western Institutional Review Board, Olympia, Wash. The patients were recruited on a first-come first-serve basis and a written informed consent was obtained from each patient at the time of enrollment. All personnel who handled and disposed of the vector observed Biosafety Level 2 compliance in accordance with the National Institutes of Health Guidelines for Research Involving Recombinant DNA molecules.
This Phase I/II trial enrolled 20 patients with metastatic gemcitabine-refractory pancreatic adenocarcinoma. Table 1 shows the patient demographics. The patients had failed a median of two regimens, one of which contained gemcitabine. All patients exhibited metastatic disease. Two patients had one target lesion, and 17 patients had 2-7 target lesions in the pancreas, lymph node, omentum, mesentery, adrenal, bone, lung, and the liver in 16 patients (Table 2). Aside from the target lesions in Table 2, all patients had either many non-target lesions, malignant ascites, pleural effusion, and peritoneal carcinomatosis. Therefore, target lesions alone may not reflect the patients' total tumor burden.
Dose Escalations: Six patients were treated at Dose Levels 0-I; 7 were treated at Dose Level II; and 7 were treated at Dose Level III. One patient was included in the Dose II cohort because he received an (FDA-approved) intrapatient dose escalation from Dose 0 to Dose II. The number of DeltaRex-G infusions, the number of completed cycles of DeltaRex-G, and the total exposure (cfu) to DeltaRex-G are summarized by dosage group in Table 3.
The median number of infusions varied from 9 in Dose Group 0-I to 52 in Dose Group III. A total of 832 infusions were administered for all patients. The total number of completed infusion cycles varied from 5 in Dose Group 0-I to 31 in Dose Group III. The median cumulative dose of DeltaRex-G increased from 9×1011 cfu in Dose Group 0-I to 60×1011 cfu in Dose Group II to 156×1011 cfu in Dose Group III. Total exposure to DeltaRex-G for all patients was 1927×1011 cfu, with a range from 30 to 453×1011 cfu.
Estimated tumor burden was determined for each patient using the following formula:
ETB (# cancer cells)=[Sum of Target Lesions (cm)+(No. of Non-Target Lesions+(20*)]×109 (Assumption: 1 cm=1×109 cancer cells).
*Note: 20×109 cancer cells for each occurrence of ascites, pleural effusion, and/or ‘too many to count’ non-target lesion.
Pretreatment evaluation included history, physical exam, complete blood count with differential and platelet count, a serum chemistry panel including aspartate transaminase, alanine transaminase, alkaline phosphatase, creatinine, and total bilirubin, assessment of coagulation status including prothrombin time, international normalized ratio, and activated partial thromboplastin time, testing for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus. All patients had a complete blood count and serum chemistry panel performed weekly during treatment. Toxicity was evaluated before each vector infusion, as well as before beginning an additional treatment cycle. Toxicity was graded using NCI CT-CAE version 339. Patients' serum was collected for detection of vector neutralizing antibodies and antibodies to gp70. The peripheral blood mononuclear cells were also collected to test for the presence of vector DNA integration and RCR at the end of 4 weeks, at 6 weeks, or before the start of a treatment cycle. Vector-related studies were performed as previously described18. DeltaRex-G was stored in volumes of 23 ml in 30 ml vials or 40 ml in 150 ml cryobags at −80° C. Preparation of the vector for patient administration consisted of rapid thawing in the vial in a 34° C. water bath 15-30 minutes prior to infusion and was given intravenously over 5-10 minutes. All personnel who handled and disposed of the vector observed Biosafety Level 2 compliance in accordance with the National Institutes of Health Guidelines for Research Involving Recombinant DNA molecules.
There were no dose-limiting toxicities observed at any dose level. Unrelated adverse events were reported for all 20 patients. Related but clinically non-significant adverse events occurred in 7 patients and all were Grade 1 (Table 4). These comprised of chills (1 patient), fatigue (2 patients) and headache (1 patient) at Dose Level II, and fatigue (4 patients) at Dose Level III. There was no treatment-related loss of hair, nausea, vomiting, anemia, thrombocytopenia, neutropenia, liver, lung or kidney dysfunction reported. There were no serious drug-related AEs.
The most frequent clinically non-significant unrelated Grade 3 AEs were hypoalbuminemia (4 patients) and increased alanine aminotransferase (3 patients). Anemia, hyperglycemia, increased aspartate aminotransferase and hypocalcemia were reported in 2 patients each. Other clinically non-significant unrelated Grade 3 AEs were reported in 1 patient each. Several types of unrelated adverse events appeared to be more frequent at higher doses: anemia, hyperbilirubinemia, increased aspartate aminotransferase and decreased appetite (Table 5). Thirteen patients experienced 25 serious adverse events, all of which were deemed not related to the study drug. Details regarding these AEs are provided in Table 6.
No patient tested positive for any of the following: vector neutralizing antibodies, antibodies to gp70, replication-competent retrovirus in peripheral blood lymphocytes (PBLs); vector integration into genomic DNA of PBLs.
To date, 19 out of the 20 patients enrolled in the study have died. None of the deaths were considered related to DeltaRex-G. The cause of death was progressive disease in all but one patient for whom the cause of death was sepsis. Remarkably, the long-term survivor exhibited lymphatic metastasis prior to intravenous DeltaRex-G infusions as salvage therapy.
Prior to beginning treatment, imaging evaluations such as whole body FDG/PET-CT scan, electrocardiography, and chest X-ray were performed. FDG PET-CT scan was done for efficacy assessment at the end of 4 weeks, at the end of 6 weeks, or before starting an additional treatment cycle up to 12 weeks, and every 12 weeks thereafter. RECISTv1.0 criteria was used to assess the tumor responses [complete response (CR); Partial response (PR); or Stable Disease (SD)]40. Tumor control rate was defined as the percentage of patients who had CR, PR or SD at any time during the DeltaRex-G treatment period. Tumor responses were also evaluated using modifications of the International PET criteria41 and the CHOI criteria42. The modified International PET Criteria defines a CR as disappearance of FDG avid uptake in target and non-target lesions with no new lesions; PR as a decrease in maximum standard uptake value of >25% from baseline with no new lesions along with no obvious progression of non-target lesions; PD as an increase in maximum standard uptake value of >25% from baseline, any new lesions, and obvious progression of non-target lesions; and SD as not meeting the criteria for CR, PR, or PD, and no symptomatic deterioration attributed to tumor progression. The modified CHOI criteria defines CR as the disappearance of all disease and no new lesions; PR as a decrease in size of ≥10% or a decrease in CT density (Hounsfeld units)≥15% with no new lesions and no obvious progression of non-measurable disease; PD as an increase in tumor size of >10% and did not meet criteria for PR by CT density, any new lesions, including new tumor nodules in a previously cystic tumor; and SD as not meeting the criteria for CR, PR, or PD, and no symptomatic deterioration attributed to tumor progression.
Of the 20 enrolled patients, fifteen received at least one complete cycle (4 weeks) of treatment and had a follow-up PET-CT scan and therefore, were considered evaluable for efficacy (modified Intent-to-Treat or mITT population) in terms of response, progression-free survival and overall survival. In the first cohort (Dose Level I), three patients were withdrawn from the study prior to completion of one treatment cycle either due to disease-related complications (n=1; worsening malignant pleural effusion) or due to a personal decision to discontinue treatment (n=2; one patient had worsening ascites, and the other decided to take alternative medicine). In the second cohort (Dose Level II), one patient had worsening ascites and clinical deterioration, and in the third cohort (Dose Level III), one patient had worsening malignant pleural effusion.
Table 7 shows evaluation of tumor response using RECIST v1.0, Choi and modified international PET Criteria in the mITT population. In the overall cohort, the median tumor burden was 32.6×109 cells; the range in tumor burden was wide across patients, with a minimum of 5.0×109 cells and a maximum of 115.5×109 cells. Notably, patients at Dose Level III had significantly larger tumor loads (52.1×109 cancer cells) than those in Dose Group 0-I or II (32.6×109 and 31.5×109 cancer cells respectively). Patients were assigned to dose levels on a first come first served basis. No significant relationship was noted between estimated tumor burden and response/PFS/OS.
By RECIST, one patient achieved a CR, two patients had a PR and 12 had SD. The tumor control rate (CR+PR+SD) by RECISTv1.0 was 100% (15/15 patients). Responses were more frequent when assessed using modified international PET criteria or Choi Criteria. By PET, one patient achieved a CR, 4 patients had a PR, and 10 patients had SD. By Choi, one patient had a CR, 5 had a PR and 8 had SD. One patient did not have a Choi analysis because the lesions were too small. By RECIST, PRs and CRs occurred only at Dose Levels II and III, suggesting a dose-dependent relationship between DeltaRex-G dose and response. PFS by RECIST was 2.7, 4.0, and 5.6 months at Dose Levels 0-I, II, and III respectively, suggesting a dose-dependent relationship between DeltaRex-G dose and PFS. Kaplan-Meier analysis of progression free survival (
aDose Level 0 = 1 × 1011 cfu BIW; Dose Level I = 1 × 1011 cfu TIW; Dose Level II = 2 × 1011 cfu TIW; Dose Level III = 3 × 1011 cfu TIW
b mITT population defined as all patients who received at least one cycle and had a follow-up PET CT scan.
cITT population defined as all patients who received at least one infusion of DeltaRex-G;
d As of Dec. 1, 2018
Table 8 shows tumor response in three patients with durable tumor response patterns when assessed by RECIST, Choi and PET (Patient 012, Patient 016, and Patient 018). Patient 012-CJP, is a 56-year-old white female, s/ρ biliary stent placement and radiation therapy for poorly differentiated PDAC, who failed gemcitabine, and had target lesions at the pancreatic head medial to the biliary stent, and right liver lobe. She achieved a best response of PR by RECIST at Week 4 and continued in PR through Week 36 (
Of note, continuation of treatment contributed to efficacy/clinical benefit in at least five patients. These patients survived from 10.6 months to 10 years after starting DeltaRex-G. Anti-tumor effects differed for individual target lesions in some patients. These data suggest that patients may benefit from extended treatment: with DeltaRex-G despite signs of apparent progression (pseudoprogression), which may result from the known mechanism of action of DeltaRex-G: induction of apoptosis via cell cycle blockade of cancer cells, tumor vasculature, and malignant tumor associated fibroblasts without bone marrow suppression, which may initially cause lesions to appear larger due to inflammatory or immunologic responses seen in published reports39, 42-43.
Median overall survival in the mITT group was calculated to be 4.3 months at Dose 0-I, 9.2 months at Dose II and 9.2 months at Dose III. The OS estimates in the efficacy evaluable mITT population among the combined group of Dose Levels 0-I was 0% at one year. In contrast, OS estimates in the combined groups Dose Levels II-III were 33.3% at one year and 25% at 1.5 years. The median OS in the ITT group was 2.6 months in the Dose 0-I cohort vs 9.0 and 7.8 months in the Dose II and III cohorts respectively. The OS rates in the Dose 0-I group was 0% at one year. In contrast, OS rates among the combined group of Dose II-III were 28.6% 1 year and 21.4% at 1.5 years (p=0.03) compared with Dose 0-I. Kaplan-Meier analysis of overall survival in the ITT population suggests a dose-response relationship between overall survival and DeltaRex-G dosage (p=0.03;
Using the one-sided Fisher Test, we compared tumor control responses (TCR by RECIST) in this advanced Phase I/II study (n=15; TCR 1 CR, 2 PR, 12 SD) with those in the prior Phase I study where patients received up to a total dose of 6×1011 CFU per cycle (TCR 1 SD, 11 PD)14. With “tumor control response” designated as CR, PR, or SD at any given time during DeltaRex-G treatment period, the proportions are 15/15 for the current study and 1/12 in the prior study, with p<0.0001 by the one-sided Fisher test. These data indicate a dose-response relationship between tumor control response (TCR) and DeltaRex-G dosage across studies.
Discussion: This report updates and extends a Phase I/II study of safety and efficacy using DeltaRex-G in gemcitabine-refractory PDAC with additional analysis and new mechanistic insights. The initial clinical data was previously reported on 13 patients by Chawla et al.19 Safety was established with no DLT following multiple DeltaRex-G infusions at all four dose levels, and the MTD was not reached. It is important to note that there was no treatment-related loss of hair, bone marrow suppression nor organ dysfunction at all dose levels. The serious adverse events experienced by these patients were probably due to disease-related complications, and not to DeltaRex-G treatment as assessed by the principal investigators. Further, there were no vector-related safety issues raised, as evidenced by no detected anti-vector neutralizing antibodies, antibodies to gp70, replication-competent retrovirus in PBLs nor vector integration into genomic DNA of PBLs. These data suggest the safety of DeltaRex-G when compared to FDA-approved therapies forepeak such as nab-paclitaxel, gemcitabine, FOLFORINOX, and erlotinib3,4,6,21-30. Regarding efficacy, we report durable response rates (3/15; 20%) lasting 36-72 weeks during DeltaRex-G treatment. Two patients were progression-free for more than one year: Patient 012 had a PFS of 13.8 months; Patient 018 had a PFS>17.9 months. The best overall response rates (20%) noted in this study were significantly better than those reported by Galanis et al.17 which used much lower DeltaRex-G doses. In support of this observation, a significant dose response relationship was shown between overall survival and DeltaRex-G dose in the Intent-to-Treat population. Remarkably, one patient is still alive 10 years later with no evidence of PDAC. The documented eradication of cancer within the lymphatic system has compelling implications that warrant additional studies of the anaplastic Signature (Sig) proteins involved44.
In conclusion, the clinical data gleaned from this Phase I/II study of precision, tumor-targeted genetic medicine suggests that (a) DeltaRex-G is exceptionally safe with a wide margin of safety, and (b) DeltaRex-G exhibits dose-dependent antitumor activity in patients with gemcitabine-refractory metastatic PDAC. Based on the analysis of clinical data, DeltaRex-G gained fast track designation from the USFDA for the conduct of a planned Phase II/III study using the optimal Dose Level III treatment schedule of DeltaRex-G versus physician's choice in a larger number of patients. This planned Phase II/III study may include correlations of CCNG1 gene expression in tumors, along with pertinent companion diagnostics, histology, and treatment outcome parameters.
All references cited in this disclosure are incorporated by reference in their entirety.
This is a continuation of International Application PCT/US2019/066968 filed on Dec. 17, 2019, which claims priority to U.S. Provisional Patent Application No. 62/780,772, filed on Dec. 17, 2018, each of which is hereby incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 62780772 | Dec 2018 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2019/066968 | Dec 2019 | US |
| Child | 17348736 | US |
