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Phase I/II Study of the Anti-Programmed Death Ligand-1 Antibody MEDI4736 in Combination With Olaparib and/or Cediranib for Advanced Solid Tumors and Advanced or Recurrent Ovarian, Triple Negative Breast, Lung, Prostate and Colorectal Cancers

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2016 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT02484404
First received: June 25, 2015
Last updated: October 20, 2016
Last verified: September 2016
  Purpose

Background:

- MEDI4736 is a drug that may help people s immune systems respond to and kill cancer cells. Olaparib is a drug that may inhibit repairing DNA damage of cancer cells. Cediranib is a drug that may stop the blood vessel growth of cancer cells. This study has two components. In the phase 1 component of the study, researchers want to investigate how well participants tolerate the combination of these drugs in treating advanced solid tumors, and in the phase 2 part of this study, researchers want to study if the combination treatments are effective in ovarian cancer.

Objectives:

  • Phase 1 part of the study: To determine the safety of the combination of MEDI4736 with the drugs olaparib or cediranib.
  • Phase 2 part of the study: To determine how effective this combination is in treating ovarian cancer.

Eligibility:

  • Phase 1 part of the study: Adults age 18 or older with advanced or recurrent solid tumors that have no standard treatment.
  • Phase 2 part of the study: Adults age 18 or older with advanced or recurrent ovarian cancer that has no standard treatment.

Design:

  • Participants will be screened with medical history, physical exam, and blood and urine tests. They will have CT or MRI scans. For these, they will lie in a machine that takes pictures of their bodies.
  • Phase 2 part of the study requests the participants to have tumor samples removed.
  • Participants will get MEDI4636 through an IV. A small plastic tube will be inserted into a vein. The drug will be given every 2 weeks for 12 months.
  • Participants will take olaparib or cediranib by mouth every day.
  • Every 28 days will be 1 cycle. For cycle 1, participants will have 2 study visits. All other cycles, they will have 1 visit. At these visits, they will repeat the screening procedures.
  • Patients will keep a drug and diarrhea diary.
  • Patients on cediranib will monitor their blood pressure and keep a blood pressure diary.
  • Participants who can become pregnant, or have a partner who can become pregnant, must practice an effective form of birth control.
  • After 12 cycles, participants will have 1-3 months of follow-up.

Condition Intervention Phase
Lung Cancer
Breast Cancer
Ovarian Cancer
Colorectal Cancer
Prostate Cancer
Triple Negative Breast Cancer
Drug: Olaparib
Drug: Cediranib
Drug: MEDI4736
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Study of the Anti-Programmed Death Ligand-1 Antibody MEDI4736 in Combination With Olaparib and/or Cediranib for Advanced Solid Tumors and Advanced or Recurrent Ovarian, Triple Negative Breast, Lung, Prostate and Colorectal Cancers

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Ph I Determine the recommended phase II dose (RP2D) and the safety of doublet therapies of MEDI4736/olaparib (MEDI-O) and MEDI4736/cediranib (MEDI-C) in patients with advanced solid tumors [ Time Frame: 28 Days ] [ Designated as safety issue: Yes ]
  • Ph II Determine overall response rate of MED-O and MEDI-C in patients with recurrent ovarian cancer [ Time Frame: Every 4 wks for Toxicity and every 8 wks for response ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 338
Study Start Date: June 2015
Estimated Study Completion Date: December 2019
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: P1 MEDI+O
Ph I MEDI4736 + olaparib dose escalation
Drug: Olaparib

Olaparib tablets will be given orally on a continuous dosing schedule. The DLT period will be one cycle, 28 days.

MEDI4736 (3mg/kg or 10mg/kg IV) and Olaparib tablets (200 mg or 300 mg BID)

Ph II - MEDI4736 + Olaparib at RP2D

Drug: MEDI4736
Ph I - MEDI4736 will be administered once every 2 weeks for 12 months.
Experimental: P1 MEDI+C
Ph I MEDI4736 + cediranib dose escalation
Drug: Cediranib

Cediranib will be given orally on a continuous dosing schedule. The DLT period will be one cycle, 28 days.

MEDI4736 (10mg/kg IV) and Cediranib (15 mg or 20 mg or 30 mg daily)

Ph II - MEDI4736 + Cediranib at RP2D

Drug: MEDI4736
Ph I - MEDI4736 will be administered once every 2 weeks for 12 months.
Experimental: P2 MEDI+O
Ph II MEDI4736 + olaparib at RP2D
Drug: Olaparib

Olaparib tablets will be given orally on a continuous dosing schedule. The DLT period will be one cycle, 28 days.

MEDI4736 (3mg/kg or 10mg/kg IV) and Olaparib tablets (200 mg or 300 mg BID)

Ph II - MEDI4736 + Olaparib at RP2D

Drug: MEDI4736
Ph I - MEDI4736 will be administered once every 2 weeks for 12 months.
Experimental: P2 MEDI+C
Ph II MEDI4736 + cediranib at RP2D
Drug: Cediranib

Cediranib will be given orally on a continuous dosing schedule. The DLT period will be one cycle, 28 days.

MEDI4736 (10mg/kg IV) and Cediranib (15 mg or 20 mg or 30 mg daily)

Ph II - MEDI4736 + Cediranib at RP2D

Drug: MEDI4736
Ph I - MEDI4736 will be administered once every 2 weeks for 12 months.
Experimental: P1 MEDI+O+C
Ph I MEDI4736 + olaparib + cediranib dose escalation
Drug: Olaparib

Olaparib tablets will be given orally on a continuous dosing schedule. The DLT period will be one cycle, 28 days.

MEDI4736 (3mg/kg or 10mg/kg IV) and Olaparib tablets (200 mg or 300 mg BID)

Ph II - MEDI4736 + Olaparib at RP2D

Drug: Cediranib

Cediranib will be given orally on a continuous dosing schedule. The DLT period will be one cycle, 28 days.

MEDI4736 (10mg/kg IV) and Cediranib (15 mg or 20 mg or 30 mg daily)

Ph II - MEDI4736 + Cediranib at RP2D

Drug: MEDI4736
Ph I - MEDI4736 will be administered once every 2 weeks for 12 months.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA GENERAL:
  • Patients must be at least 18 years of age.
  • Patients must have adequately controlled blood pressure on a maximum of three antihypertensive medications.
  • Patients who have the following clinical conditions are considered to be at increased risk for cardiac toxicities. Patients with any cardiac history of the following conditions within 1 year prior to study enrollment are excluded from the study:

    • Prior events including myocardial infarction, pericardial effusion, and myocarditis.
    • Prior cardiac arrhythmia including atrial fibrillation and atrial flutter, or requiring concurrent use of drugs or biologics with pro-arrhythmic potential.
    • NYHA Class II or greater heart failure.
    • If cardiac function assessment is clinically indicated or performed, an LVEF less than normal per institutional guidelines, or <55%, if threshold for normal is not otherwise specified by institutional guidelines.
    • QTc prolongation >470 msec or other significant ECG abnormality noted within 14 days of treatment.
    • Hypertensive crisis or hypertensive encephalopathy.
    • Clinically significant peripheral vascular disease or vascular disease, including rapidly growing aortic aneurysm or abdominal aortic aneurysm >5 cm or aortic dissection.
    • Unstable angina.
  • Eligibility for patients with asymptomatic and a previous diagnosis of immune or inflammatory colitis, or patients with chronic diarrhea > 1 month without immune or inflammatory colitis is a PI decision on an individual patient basis.
  • Patients with a history of cerebrovascular accident or transient ischemic attack within 1 year prior to study enrollment are not eligible.
  • Patients with a history of previous clinical diagnosis of tuberculosis are not eligible.
  • Patients with a history of auto-immune disease requiring steroid maintenance, or history of primary immunodeficiency are not eligible.
  • HIV-positive patients on antiretroviral therapy are ineligible because of potential pharmacokinetic interactions with study drugs.
  • HBV-or HCV-positive patients are ineligible because of potential reactivation of hepatitis virus following steroids.
  • Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEDI4736, olaparib, cediranib, or to other humanized monoclonal antibodies, or a history of anaphylaxis, angioedema, laryngeal edema, serum sickness, or uncontrolled asthma, are not eligible.
  • Patients who have had prior immune checkpoint inhibitors, such as MEDI4736 or other PD1 or PD-L1 inhibitors or an anti-CTLA4 therapy are not eligible.
  • Pregnant and breastfeeding women are excluded from this study.
  • Patients with any other concomitant or prior invasive malignancies are ineligible.

PHASE I STUDY ELIGIBILITY CRITERIA

  • Patients must have histologically or cytologically confirmed advanced solid tumor that is refractory to standard treatment or for which no standard treatment exists, with evaluable disease.
  • Patients are allowed to have received prior PARP inhibitors (PARPi), and/or anti-angiogenesis therapy. However, patients who were treated with both olaparib and cediranib, either in combination or sequentially are not eligible. For this study, BSI-201 (iniparib) is not considered as PARPi.

PHASE II MEDI4736 PLUS OLAPARIB OR CEDIRANIB STUDY ELIGIBILITY CRITERIA - OVARIAN CANCER

  • Patients must have histologically or cytologically confirmed persistent or recurrent ovarian, fallopian tube, or primary peritoneal cancer and have received at least two prior platinum-containing regimens or who are platinum resistant or refractory during or after a first platinum containing regimen.
  • Patients must have at least one lesion deemed safe to biopsy and be willing to undergo a mandatory baseline biopsy.
  • Patients are allowed to have received prior PARPi, and/or anti-angiogenesis therapy including but not limited to thalidomide, bevacizumab, sunitinib, sorafenib, or other anti-angiogenics. However, patients who were treated with both olaparib and cediranib, either in combination or sequentially are not eligible. For this study, BSI-201 (iniparib) is not considered as PARPi.

PHASE II STUDY MEDI4736 PLUS OLAPARIB ELIGIBILITY CRITERIA TRIPLE NEGATIVE BREAST CANCER

  • Patients must have histologically confirmed persistent or recurrent triple-negative breast cancer (TNBC)
  • ER/PR/HER2 status needs to be documented either by an outside source or at NCI.
  • Documentation of germline BRCA1 and BRCA2 mutation (gBRCAm) status will be required for eligibility.
  • Patients must have measurable disease as defined by RECIST v1.1.
  • Patients must have at least one lesion deemed safe to biopsy and be willing to undergo a mandatory baseline biopsy.
  • Patients who have received more than three lines of prior therapy in the metastatic or recurrent settings are not eligible.
  • Patients who have received prior PARPi or immune checkpoint inhibitors are ineligible.

PHASE II MEDI4736 PLUS OLAPARIB OR CEDIRANIB STUDY ELIGIBILITY CRITERIA - NON-SMALL CELL LUNG CANCER

  • Histologically or cytologically confirmed advanced NSCLC with at least one prior line of platinum-based chemotherapy (or treatment with EGFR or ALK tyrosine kinase inhibitors if tumors harbor an EGFR-sensitizing mutation or ALK translocation respectively).
  • Patients must have measurable disease as defined by RECIST v1.1.
  • Patients must have at least one lesion deemed safe to biopsy and be willing to undergo a mandatory baseline biopsy.
  • Patients who have received anti-angiogenesis therapy are eligible. However, patients who were treated with cediranib, either in combination or monotherapy are not eligible.
  • Patients who have had prior PARPi are not eligible.
  • Patients who have received more than three lines of prior therapy in the metastatic or recurrent settings are not eligible.
  • Patients with prior history of pneumonitis and/or interstitial lung disease will be excluded.

PHASE II MEDI4736 PLUS OLAPARIB STUDY ELIGIBILITY CRITERIA - SMALL CELL LUNG CANCER

  • Histologically or cytologically confirmed SCLC with at least one prior line of platinum-based chemotherapy are eligible. Patients with both platinum-sensitive and platinum-refractory disease will be eligible.
  • Patients must have measurable disease as defined by RECIST v1.1.
  • Patients must have at least one lesion deemed safe to biopsy and be willing to undergo a mandatory baseline biopsy.
  • Patients who have received anti-angiogenesis therapy are eligible. However, patients who were treated with cediranib, either in combination or monotherapy are not eligible.
  • Patients who have had prior PARPi are not eligible.
  • Patients who have received more than three lines of prior therapy in the metastatic or recurrent settings are not eligible.
  • Patients with any other concomitant or prior invasive malignancies are ineligible. Patients with prior history of pneumonitis and/or interstitial lung disease will be excluded.

PHASE II MEDI4736 PLUS OLAPARIB STUDY ELIGIBILITY CRITERIA - METASTATIC CASTRATE-RESISTANT PROSTATE CANCER

  • Patients must have metastatic, progressive, castrate resistant prostate cancer (mCRPC).
  • All patients must have at least one lesion deemed safe to biopsy and be willing to undergo a mandatory baseline biopsy.
  • Patients must have received prior treatment with enzalutamide and/or abiraterone.
  • Patients must have undergone bilateral surgical castration or must agree to continue on GnRH agonists/antagonists for the duration of the study.
  • Patients who have had treatment with docetaxel for the treatment of metastatic castrate-sensitive prostate cancer within 6 months before the first dose of study treatment are not eligible.
  • Patients who have had progression of prostate cancer on prior docetaxel treatment for castrate sensitive disease are ineligible.
  • Patients who have had prior treatment with PARPi are not eligible.
  • Patients who have received radionuclide treatment within 6 weeks prior to the first dose of the study treatment are not eligible.
  • Patients with any other concomitant or prior invasive malignancies are ineligible.

PHASE II MEDI4736 PLUS CEDIRANIB ELIGIBILITY CRITERIA - COLORECTAL CANCER

  • Histologically or cytologically confirmed advanced colorectal cancer. Patients must have progressed on, been intolerant of or refused prior oxaliplatin- and irinotecan-containing chemotherapeutic regimen, and have disease that is not amenable to potentially curative resection. Patients who have a known KRAS wild type tumor must have progressed, been intolerant of or refused cetuximab or panitumumab-based chemotherapy.
  • Patients are allowed to have received prior anti-angiogenesis therapy with the exception of prior cediranib. However, patients must not have received other anti-angiogenesis therap(ies) within 6 months prior to study enrollment.
  • Patients must be MSI-stable (or low).
  • Patients must have at least one focus of metastatic disease that is amenable to pre-and on-treatment biopsy.
  • Patients who were previously treated with cediranib are ineligible.
  • Patients with any other concomitant or prior invasive malignancies are ineligible.
  • Patients with prior history of pneumonitis and/or interstitial lung disease will be excluded.

Additional eligibility criteria may apply as defined per protocol.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02484404

Contacts
Contact: Irene Ekwede, R.N. (301) 435-4859 ekwedeib@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Jung-Min Lee, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02484404     History of Changes
Other Study ID Numbers: 150145  15-C-0145 
Study First Received: June 25, 2015
Last Updated: October 20, 2016
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Immune Checkpoint Inhibitor
PARP Inhibitor
VEGFR Inhibitor

Additional relevant MeSH terms:
Protein Kinase Inhibitors
Enzyme Inhibitors
Poly(ADP-ribose) Polymerase Inhibitors
Breast Neoplasms
Colorectal Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Antibodies
Antibodies, Monoclonal
Cediranib
Olaparib
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on December 06, 2016