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

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ClinicalTrials.gov Identifier: NCT02826486
Recruitment Status : Active, not recruiting
First Posted : July 11, 2016
Last Update Posted : January 9, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
BioLineRx, Ltd.

Brief Summary:
This study will assess the efficacy and safety of BL-8040 as a single agent and in combination with pembrolizumab (Keytruda®) in subjects with metastatic pancreatic adenocarcinoma.

Condition or disease Intervention/treatment Phase
Metastatic Pancreatic Adenocarcinoma Drug: BL-8040 Drug: BL-8040 plus pembrolizumab Phase 2

Detailed Description:

This will be an open-label, single arm, phase IIa study in subjects with metastatic pancreatic adenocarcinoma.

The study will include 30 subjects with unresectable metastatic pancreatic adenocarcinoma.

The study consists of two periods:

  • Monotherapy period: One week, with BL-8040 administered daily on days 1-5.
  • Combination therapy: Three week cycles of a combination of BL-8040 administered three times a week (TIW) and pembrolizumab administered once every three weeks.

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 (1.25 mg/kg) three times a week (TIW) and pembrolizumab (200mg) once every three weeks. The combination therapy will continue for up to two years, or until progression, clinical deterioration or early termination, whichever comes first.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 37 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II, Multicenter, Open-label Single Arm Study to Assess the Safety and Efficacy of the Combination of BL-8040 and Pembrolizumab in Patients With Metastatic Pancreatic Cancer, the COMBAT Study
Actual Study Start Date : September 2016
Estimated Primary Completion Date : June 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: BL-8040 plus pembrolizumab (Keytruda®)

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 repeated 3 week long cycles of 200 mg pembrolizumab administered by intravenous infusion (IV) on day 1 of each cycle plus SC injections of BL-8040 1.25 mg/kg three times a week on non-consecutive days.

Drug: BL-8040
BL-8040 1.25 mg/kg subcutaneous(SC) injections

Drug: BL-8040 plus pembrolizumab
pembrolizumab will be given as a 30-minute IV infusion
Other Name: BL-8040 plus keytruda




Primary Outcome Measures :
  1. Objective response rate (ORR) assessed by imaging according to RECIST 1.1 criteria [ Time Frame: 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. ]
    response is determined by assessment of target lesions identified in CT or MRI imaging


Secondary Outcome Measures :
  1. Objective response rate (ORR) assessed by imaging according to irRECIST [ Time Frame: 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. ]
    repeat imaging will be done for confirmation of initial progressive disease

  2. Overall survival [ Time Frame: Through study completion, an average of 2 years, and follow-up until date of death up to 100 weeks. ]
  3. Progression-free survival (PFS) by imaging (RECIST 1.1) [ Time Frame: through study completion, an average of 2 years ]
    imaging will be assessed according to RECIST 1.1

  4. Progression-free survival (PFS) by imaging (irRECIST) [ Time Frame: through study completion, an average of 2 years ]
    imaging will be assessed according to irRECIST

  5. Duration of response [ Time Frame: through study completion, an average of 2 years, and follow-up until the date of progression up to 100 weeks. ]

Other Outcome Measures:
  1. Safety as measured by number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment with BL-8040 alone or in combination with pembrolizumab [ Time Frame: study treatment duration, up to 2 years ]
    safety assessment based on CTCAE version 4.03 criteria for adverse events and clinical laboratory parameters

  2. Tolerability of BL-8040 as monotherapy and in combination with pembrolizumab by review of adverse events and clinical laboratory parameters [ Time Frame: study treatment duration, up to 2 years ]

    Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment)

    Assessment based on CTCAE version 4.03 criteria for adverse events and clinical laboratory parameters.


  3. Incidence of early discontinuation of subjects. [ Time Frame: study treatment duration, up to 2 years ]
    discontinuation of study treatment for any reason

  4. Incidence of early discontinuation due to adverse events. [ Time Frame: study treatment duration, up to 2 years + 90 days for SAE follow-up ]
    adverse events will be recorded based on CTCAE version 4.03 criteria and MedDRA



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 18 years and older.
  2. Patients must sign a written informed consent prior to entering the study.
  3. Histologically confirmed (either previously or newly biopsied) metastatic unresectable pancreatic adenocarcinoma, including with intraductal papillary mucinous neoplasm.
  4. Have measurable disease (≥ 1 measurable lesion) based on 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.
  5. Subjects with one or more prior treatments for their pancreatic cancer.
  6. 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
  7. 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.
  8. ECOG status ≤1.
  9. Life expectancy of at least 3 months.
  10. Adequate organ function at baseline as defined below. All laboratory assessments should be performed within 10 days of treatment initiation.

    1. Hematological:

      • WBC ≥ 2,500/mm^3
      • Absolute neutrophil count ≥ 1000 /mm^3
      • Platelet count ≥ 100,000/mm^3
      • Hemoglobin ≥9 g/dL or ≥5.6 mmol/L
      • Hematocrit ≥30%
    2. Renal function:

      Creatinine ≤1.5x 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 subjects with creatinine levels > 1.5x institutional ULN

    3. Hepatic function:

      • Total Bilirubin: ≤1.5xULN OR Direct bilirubin ≤ULN for subjects with total bilirubin levels >1.5xULN
      • AST (SGOT) and ALT (SGPT): ≤2.5xULN OR ≤5xULN for subjects with liver metastases
    4. 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
      • aPTT: ≤1.5xULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  11. Subjects must use effective contraception:

    1. 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
      • Amenorrheic 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
    2. 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:

  1. Has 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.
  2. Has an active infection requiring systemic therapy or uncontrolled infection.
  3. 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.
  4. Has an Underlying medical condition that would preclude study participation.
  5. Has a disease that is suitable for therapy administered with curative intent.
  6. 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.
  7. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within seven days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
  8. Has had a prior anti-cancer monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to agents administered more than 4 weeks earlier.
  9. 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 AEs due to a previously administered agent .
  10. An active autoimmune disease that has required systemic treatment in the two years preceding the study (i.e. with the use of disease-modifying agents, corticosteroids or immunosuppressive drugs). 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.
  11. Has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoetin) within four weeks prior to study Day 1.
  12. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
  13. Has a history of interstitial lung disease.
  14. O2 saturation < 92% (on room air).
  15. 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.
  16. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  17. 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.
  18. 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.
  19. Has a known history of HIV (HIV 1/2 antibodies).
  20. Has known active Hepatitis B (e.g., Hepatitis B Surface Antigen [HBsAg] reactive) or Hepatitis C (e.g., Hepatitis C Virus [HCV] RNA [qualitative] is detected).
  21. Has known history of Chronic Hepatitis B or C
  22. 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.
  23. 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 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 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02826486


Locations
United States, Arizona
Mayo Clinic
Phoenix, Arizona, United States, 85054
Honor Health
Scottsdale, Arizona, United States, 85258
United States, Louisiana
Ochsner Medical Center
New Orleans, Louisiana, United States, 70121
United States, Massachusetts
DF/HCC
Boston, Massachusetts, United States, 02215
United States, Missouri
Washington University of St Louis
Saint Louis, Missouri, United States, 63110
United States, Texas
Baylor Charles A. Sammons Cancer Center
Dallas, Texas, United States, 75246
Israel
Rambam Medical Center
Haifa, Israel
Rabin Medical Center
Petaẖ Tiqwa, Israel
Chaim Sheba Medical Center
Ramat Gan, Israel
Sourasky Medical Center
Tel Aviv, Israel
Sponsors and Collaborators
BioLineRx, Ltd.
Merck Sharp & Dohme Corp.
Investigators
Study Chair: Abi Vainstein, MD BioLineRx, Ltd.

Responsible Party: BioLineRx, Ltd.
ClinicalTrials.gov Identifier: NCT02826486     History of Changes
Other Study ID Numbers: BL-8040.PAC.201
First Posted: July 11, 2016    Key Record Dates
Last Update Posted: January 9, 2018
Last Verified: February 2017

Additional relevant MeSH terms:
Adenocarcinoma
Pancreatic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Pembrolizumab
Antineoplastic Agents