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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02484404
Recruitment Status : Recruiting
First Posted : June 29, 2015
Last Update Posted : August 14, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

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 2 part of the study: To determine how effective this combination is in treating ovarian cancer.

Eligibility:

- 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 4 weeks until disease progression.
  • 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 or disease Intervention/treatment Phase
Colorectal Neoplasms Breast Neoplasms Drug: Olaparib Drug: Cediranib Drug: MEDI4736 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 384 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (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
Actual Study Start Date : June 29, 2015
Estimated Primary Completion Date : January 29, 2022
Estimated Study Completion Date : December 29, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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: 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+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.

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: 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+O+C
Ph II MEDI4736 + olaparib + cediranib 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: 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.




Primary Outcome Measures :
  1. 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 ]
    Determination of the recommended phase II dose (RP2D) Safety: number of Adverse events

  2. 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 ]
    Overall response rate


Secondary Outcome Measures :
  1. Ph I doublet tx: determin the safety of the doublets, MEDI+O and MEDI+C [ Time Frame: every 28 days ]
    Safety: number of Adverse events

  2. Ph I doublet tx:determine preliminary response rates of the doublets using RECIST v1.1 [ Time Frame: every 8 weeks ]
    Response : Preliminary response rate

  3. Ph I doublet tx: determine the pharmacokinetics of the doublets and correlate with safety. [ Time Frame: Cycle 1 Days 1 and 15; Cycles 2 and beyond Day 1 ]
    Pharmacokinetics + Safety: adverse events

  4. Ph I doublet tx: explore changes in peripheral immune subsets, plasma cytokines and circulating endothelial cells with safety and/or clinical outcome of MEDI+C [ Time Frame: every 28 days ]
    Correlative laboratory research results + safety (adverse events) and/or clinical outcome

  5. Ph I doublet:determine the potential relationship between PD-L1 expression obtained from archival tissue samples and clinical response [ Time Frame: every 28 days ]
    PD-L1 expression obtained from archival tissue samples and clinical response

  6. Ph I of triplet tx: determine the safety of MEDI+O+C [ Time Frame: every 28 days ]
    Safety (adverse events)

  7. Ph I of triplet tx: determine preliminary response rates of MEDI+O+C using RECIST v1.1 [ Time Frame: every 8 weeks ]
    Response: Preliminary response rate

  8. Ph I of triplet tx:determine the pharmacokinetics of the triplet and correlate with safety. [ Time Frame: Cycle 1 Days 1 and 15; Cycles 2 and beyond Day 1 ]
    Pharmacokinetics + Safety: adverse events

  9. Ph I of triplet tx: explore changes in peripheral immune subsets, plasma cytokines and circulating endothelial cells with safety and/or clinical outcome of MEDI+O+C [ Time Frame: every 28 days ]
    Correlative laboratory research results + safety (adverse events) and/or clinical outcome

  10. Ph I of triplet tx: determine the potential relationship between PD-L1 expression obtained from archival tissue samples and clinical response [ Time Frame: every 28 days ]
    PD-L1 expression obtained from archival tissue samples and clinical response

  11. Ph II Cohort 1 OvCa; MEDI+O, MEDI+C and MEDI+O+C arms: To evaluate PFS, safety by CTCAE v4.0, and potential relationship between pretreatment tumor PD-L1 expression obtained from biopsies and clinical response [ Time Frame: every 28 days, every 8 weeks ]
    Progression-Free Survival (PFS) + safety (adverse events) + PD-L1 expression ontained from biopsies and clinical response

  12. Ph II Cohort 2 NSCLC; MEDI+O and MEDI+C arms: To determine ORR, and safety by CTCAE v4.0 [ Time Frame: every 28 days, every 8 weeks ]
    ORR + Safety (adverse events)

  13. Ph II Cohort 3 SCLC; MEDI+O arm: To determine PFS and safety by CTCAE v4.0 [ Time Frame: every 28 days, every 8 weeks ]
    PFS + Safety (adverse events)

  14. Ph II Cohort 4 mCRPC; MEDI+O arm: To determine ORR, safety by CTCAE v4.0, duration of response and PSA responses. [ Time Frame: every 28 days, every 8 weeks ]
    ORR + safety (adverse events), duration of response and PSA responses.

  15. Ph II Cohort 5 TNBC; MEDI+O arm: To determine PFS, safety by CTCAE v4.0, and potential relationship between pretreatment tumor PD-L1 expression obtained from biopsies and clinical response [ Time Frame: every 28 days, every 8 weeks ]
    ORR + safety (adverse events)



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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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
  • ELIGIBILITY:

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, however, patients with long-standing (>5 years) HIV on antiretroviral therapy > 1 month (undetectable HIV viral load and CD4 count > 150 cells/microL) may be eligible if the PI determines no anticipated clinically significant drug-drug interactions.
    • 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 eligible.
    • Pregnant and breastfeeding women are excluded from this study.
    • Patients with any other concomitant or prior invasive malignancies are ineligible.

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 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 prior PARPi are ineligible.
  • Patients must not have evidence of CNS metastasis or leptomeningeal disease within one year prior to enrollment.

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, ALK, or BRAF-targeted tyrosine kinase inhibitors if tumors harbor an EGFR-sensitizing mutation, ALK translocation, or BRAF V600E mutation, 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, including but not limited to thalidomide, bevacizumab, sunitinib, sorafenib, or other anti-angiogenics. However, patients who were treated with cediranib, either in combination or monotherapy are not eligible.
  • Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone or an equivalent corticosteroid.
  • Patients who have had prior PARPi 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 - 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 with the exception of patients who were treated with docetaxel and androgen deprivation therapy for metastatic castrate-sensitive prostate cancer and progressed on docetaxel treatment or who progress within one month of the last docetaxel dose.
  • 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 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.

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): NCT02484404


Contacts
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Contact: Erin K Villanueva (Nichols) (240) 760-6131 erin.nichols@nih.gov

Locations
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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
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Principal Investigator: Jung-Min Lee, M.D. National Cancer Institute (NCI)
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02484404    
Other Study ID Numbers: 150145
15-C-0145
First Posted: June 29, 2015    Key Record Dates
Last Update Posted: August 14, 2020
Last Verified: August 7, 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Immune Checkpoint Inhibitor
PARP Inhibitor
VEGFR Inhibitor
Additional relevant MeSH terms:
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Colorectal Neoplasms
Breast Neoplasms
Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Breast Diseases
Skin Diseases
Durvalumab
Olaparib
Cediranib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors