Study Assessing Safety and Efficacy of Combination of BL-8040 and Pembrolizumab in Metastatic Pancreatic Cancer Patients (COMBAT/KEYNOTE-202)

Study Overview
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Brief Summary
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This study will assess the efficacy and safety of BL-8040 in combination with pembrolizumab (Keytruda®) and BL8040/ Pembrolizumab in combination with liposomal irinotecan (Onivyde®)/5-fluorouracil/leucovorin (5-FU/LV) in subjects with metastatic pancreatic adenocarcinoma.

Detailed Description
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This will be an open-label, two-cohort, phase IIa study in subjects with metastatic pancreatic adenocarcinoma. The study will be comprised of 2 cohorts,. Each includes approximately 40 subjects with unresectable metastatic pancreatic adenocarcinoma. Each cohort study consists of two periods: Monotherapy period: One week, with BL-8040 administered daily on days 1-5. Combination therapy: Cohort 1: Three-week cycles of a combination of BL-8040 administered three times a week (TIW) and pembrolizumab administered once every three weeks. Cohort 2: Onivyde®/5-FU/LV every 2 weeks, pembrolizumab once every 3 weeks and BL-8040 twice a week. Cohort 1: Subjects with metastatic pancreatic adenocarcinoma will be enrolled and receive BL-8040 monotherapy for five days followed by a combination treatment of BL-8040 and pembrolizumab. During the monotherapy period, eligible subjects will receive daily subcutaneous (SC) injections of BL-8040 (1.25 mg/kg) on Days 1 - 5. From Day 8, subjects will begin a combination period consisting of treatment with SC BL-8040 TIW and pembrolizumab once every three weeks. The combination therapy will continue for up to 35 cycles of pembrolizumab approximately two years), or until progression, clinical deterioration or Early Termination, whichever comes first. Cohort 2: Subjects with metastatic pancreatic adenocarcinoma that have progressed following first-line treatment with gemcitabine-based chemotherapy will be enrolled and receive BL-8040 monotherapy for five days followed by a combination treatment of BL-8040, pembrolizumab and chemotherapy. During the monotherapy period, eligible subjects will receive daily SC injections of BL-8040 on Days 1 - 5. From Day 8, subjects will begin a combination period consisting of: IV Onivyde® followed by IV leucovorin (LV), followed by IV fluorouracil (5-FU), every 2 weeks. Pembrolizumab every three weeks. BL-8040 twice a week The combination therapy will continue for up to 35 treatments (approximately two years), or until progression, clinical deterioration or Early Termination, whichever comes first.

Official Title
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A Phase IIa, Multicenter, Open-label Study to Assess the Safety and Efficacy of the Combination of BL-8040 and Pembrolizumab in Patients With Metastatic Pancreatic Cancer, the COMBAT Study

Conditions
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Metastatic Pancreatic Adenocarcinoma

Intervention / Treatment
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* Drug: BL-8040
* Drug: Pembrolizumab
* Drug: Chemotherapy of Onivyde


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years and older. Patients must sign a written informed consent prior to entering the study. Histologically confirmed (either previously or newly biopsied) metastatic unresectable pancreatic adenocarcinoma, including with intraductal papillary mucinous neoplasm. Have measurable disease (≥ 1 measurable lesion) based on Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 as determined by the site study team. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Previous treatment lines Cohort 1: Have documented objective radiographic progression after stopping treatment with first-line or further therapy, i.e. chemotherapy and or radiotherapy. Surgery not followed with neoadjuvant therapy will not be considered as first-line therapy. Cohort 2: Have documented objective radiographic progression after stopping treatment with first-line, gemcitabine-based chemotherapy. Only primary metastatic patients will be allowed to participate. Patients with previous surgery for their pancreatic cancer will not be allowed to participate. Willing to submit an evaluable tumor tissue sample, preferably from a liver metastasis, unless tumor is considered inaccessible or biopsy is otherwise considered not in the subject's best interest Complete resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less (except alopecia). If the subject received major surgery or radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or complications from the intervention. ECOG status ≤1. Life expectancy of at least 3 months. Adequate organ function at Baseline as defined below. All laboratory assessments should be performed within 10 days of treatment initiation Hematological: White blood cell (WBC) ≥ 2,500/mm^3 Absolute neutrophil count Cohort 1: ≥ 1000 /mm^3 Cohort 2: ≥ 1500 /mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥9 g/dL or ≥5.6 mmol/L Hematocrit ≥30% Renal function: • Creatinine ≤1.5x Upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR]) can also be used in place of creatinine or (CrCl) > 60 mL/min for subject with creatinine levels > 1.5x institutional ULN Hepatic function: Total Bilirubin: within institutional normal ranges Aspartate Aminotransferase/Serum Glutamic Oxaloacetic Transaminase (AST/SGOT) and Alanine Transaminase/Serum Glutamic Pyruvic Transaminase (ALT/SGPT): ≤2.5xULN OR ≤5xULN for subjects with liver metastases Coagulation: INR or PT: ≤1.5xULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT): ≤1.5xULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Subjects must use effective contraception: Female subjects must be of non-childbearing potential or, if of childbearing potential, must have a negative urine or serum pregnancy test within 72 hours prior to taking study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the subject to be eligible. Non-childbearing potential is defined as (by other than medical reasons): ≥45 years of age and has not had menses for over 2 years Amenorrhoeic for > 2 years without a hysterectomy and oophorectomy and a Follicle Stimulating Hormone (FSH) value in the postmenopausal range upon pretrial (Screening) evaluation Post hysterectomy, bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation at least 6 weeks prior to Screening. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure otherwise the subject must be willing to use two adequate barrier methods throughout the study, starting with the Screening visit through 120 days after the last dose of study therapy. Information must be captured appropriately within the site's source documents Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. Exclusion Criteria: Has a pancreatic tumor other than adenocarcinoma, including: acinar cell carcinoma, pancreaticoblastoma, malignant cystic neoplasms, endocrine neoplasms, squamous cell carcinoma, Vater and periampullary duodenal or common bile duct malignancies. For Cohort 2 only: subjects with a bowel obstruction. Has an active infection requiring systemic therapy or has an uncontrolled infection. Has a known additional malignancy that is progressing or requires active treatment. Exceptions are adequately treated basal cell or squamous cell carcinoma that has undergone potentially curative therapy or carcinoma in situ of the cervix. Has an underlying medical condition that would preclude study participation. Has a disease that is suitable for therapy administered with curative intent. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at Baseline) from AE due to agents administered more than 4 weeks earlier. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or has not recovered (i.e., ≤ Grade 1 or at Baseline) from AE due to a previously administered agent . An active autoimmune disease that has required systemic treatment in the 2 years preceding the study (i.e., with the use of disease-modifying agents, corticosteroids or immunosuppressive drugs). Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed. Has received transfusions of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including Granulocyte Colony Stimulating Factor [G-CSF], GM-CSF or recombinant erythropoietin) within 4 weeks prior to study Day 1. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. Has a history of interstitial lung disease. O2 saturation < 92% (on room air). For both Cohorts: Has unstable angina, new onset angina within the last 3 months, myocardial infarction within the last 6 months, and current congestive heart failure New York Heart Association Class III or higher. For Cohort 2: has ventricular arrhythmias or uncontrolled blood pressure, or severe arterial thromboembolic events less than 6 months prior to study initiation. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the Screening visit through 120 days after the last dose of trial treatment. Women with a positive pregnancy test within 72 hours from Baseline. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or if the subject has previously participated in Merck MK-3475 clinical trials. Has a positive HIV test at Screening or at any time prior to Screening. Patients without a prior positive HIV test result will undergo an HIV test at Screening, unless not permitted per local regulations. Has known active Hepatitis B (defined as having a positive Hepatitis B surface antigen (HBsAg) test at Screening) or Hepatitis C (defined as having a positive HCV antibody test or a positive HCV RNA test at Screening) Has known history of Chronic Hepatitis B or C Has received a live vaccine within 30 days of the planned start of study therapy. Seasonal flu vaccines that do not contain live virus are permitted. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging using the identical imaging modality for each assessment, either MRI or computerized tomography (CT) scan, for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to Baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 14 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. Cohort 2: Has clinical ascites requiring treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BL-8040 plus pembrolizumab (Keytruda®)<br>BL-8040 monotherapy 1.25 mg/kg subcutaneous(SC) injections daily on days 1-5 of week 1 of treatment. Combination therapy period begins following monotherapy treatment and consists of: Pembrolizumab 200mg once every three weeks. Beginning on Day 10, BL-8040 three times a week | Drug: BL-8040<br>* BL-8040 subcutaneous(SC) injections<br>Drug: Pembrolizumab<br>* pembrolizumab will be given as a 30-minute IV infusion<br>* Other names: Keytruda;|
| Experimental: BL-8040 plus pembrolizumab (Keytruda®) plus Onivyde chemo<br>BL-8040 monotherapy 1.25 mg/kg subcutaneous(SC) injections daily on days 1-5 of week 1 of treatment. Combination therapy period begins following monotherapy treatment and consists of: IV Onivyde® 70 mg/m2 over 90 minutes followed by IV leucovorin (LV) 400 mg/m2 over 30 minutes or according to local standard, followed by IV fluorouracil (5-FU) 2400 mg/m2 over 46 hours, every 2 weeks. Pembrolizumab 200mg once every three weeks. Beginning on Day 10, BL-8040 twice a week and following the chemotherapy dosing. | Drug: BL-8040<br>* BL-8040 subcutaneous(SC) injections<br>Drug: Pembrolizumab<br>* pembrolizumab will be given as a 30-minute IV infusion<br>* Other names: Keytruda;Drug: Chemotherapy of Onivyde<br>* • IV Onivyde® followed by IV leucovorin (LV), followed by IV fluorouracil (5-FU), every 2 weeks.<br>* Other names: Onivyde / Leucovorin (LV) / 5FU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) assessed by imaging according to RECIST 1.1 criteria | response is determined by assessment of target lesions identified in CT or MRI imaging | Change in response between screening, end of monotherapy (Day 5), end of cycle 2 (Day 28) and approximately every 63 days until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) assessed by imaging according to irRECIST | repeat imaging will be done for confirmation of initial progressive disease | Change in response between screening, end of monotherapy (Day 5), end of cycle 2 (Day 28) and every 63 days until the date of confirmed progression assessed up to 2 years, or date of death from any cause. | 
| Overall survival |  | Through study completion, an average of 2 years, and follow-up until date of death up to 100 weeks. | 
| Progression-free survival (PFS) by imaging (RECIST 1.1) | imaging will be assessed according to RECIST 1.1 | through study completion, an average of 2 years | 
| Disease Control | Sum of PRs, CRs and SDs | through study completion, an average of 2 years |