Phase I/II Study of the Anti-Programmed Death Ligand-1 Durvalumab 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 Can...

STATUS

Recruiting
End date

Dec 30, 2025
participants needed

384
sponsor

National Cancer Institute (NCI)

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Updated on 29 August 2023

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cancer

tyrosine

monoclonal antibodies

measurable disease

breast cancer

lung cancer

unstable angina

BRAF

metastasis

HER2

EGFR

bevacizumab

docetaxel

cancer chemotherapy

solid tumour

triple negative breast cancer

olaparib

erbb2

BRCA1

BRCA2

fallopian tube

asthma

platinum-based chemotherapy

mammogram

health screening

peritoneal cancer

recurrent ovarian cancer

cancer of the ovary

lung carcinoma

Summary

Background

Durvalumab 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 Durvalumab 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.

Description

Background

Disruption of the immune checkpoint PD-1/PD-L1 pathway yielded clinical activity in subsets of advanced solid tumors, such as melanoma and lung cancer.

Olaparib (O), a PARP inhibitor (PARPi), has demonstrated single agent activity in recurrent ovarian cancer (OvCa), and subsets of prostate, triple negative breast or lung cancers.

Our recent randomized phase 2 study showed that O and cediranib (C), a VEGFR1-3 inhibitor was clinically superior to O alone in platinum-sensitive recurrent OvCa.

We hypothesize that increased DNA damage by PARP inhibition and/or reduced angiogenesis by VEGFR inhibition will complement the anti-tumor activity of an immune checkpoint inhibitor, Durvalumab, in recurrent OvCa and other solid tumors.

Objectives

Phase I: To determine the recommended phase II dose (RP2D) and the safety of doublet therapies (Durvalumab/olaparib [Durvalumab+O] and Durvalumab/cediranib [Durvalumab+C]) and triplet therapy (Durvalumab+O+C) in patients with advanced solid tumors.

Phase II Cohort 2 non-small cell lung cancer (NSCLC); Durvalumab+O and Durvalumab+C arms: To determine clinical efficacy as measured by progression-free survival (PFS)

Phase II Cohort 3 small cell lung cancer (SCLC); Durvalumab+O arm: To determine clinical efficacy as measured by ORR

Phase II Cohort 4 metasttaic castrate-resistant prostate cancer (mCRPC); Durvalumab+O arm: To determine clinical efficacy as measured by PFS

Phase II Cohort 5 triple negative breast cancer (TNBC); Durvalumab+O arm: To determine clinical efficacy as measured by ORR

Phase II Cohort 1 OvCa; Durvalumab+O, Durvalumab+C and Durvalumab+O+C arms: To determine clinical efficacy as measured by overall response rate (ORR)

Phase II Cohort 6 colorectal cancer (CRC): C+Durvalumab arm: To determine clinical efficacy as measured by PFS

Eligibility

Phase I: Advanced or recurrent solid tumors with evaluable disease.

Phase II Cohort 1 Durvalumab+O, Durvalumab+C and Durvalumab+O+C arms: Advanced or recurrent OvCa

Phase II Cohort 2 Durvalumab+O and Durvalumab+C arms: Advanced or recurrent NSCLC

Phase II Cohort 3 Durvalumab+O arm: Advanced or recurrent SCLC

Phase II Cohort 4 Durvalumab+O arm: mCRPC

Phase II Cohort 5 Durvalumab+O arm: Advanced or recurrent TNBC

Phase II Cohort 6 C+Durvalumab arm: Advanced or recurrent CRC

Patients must be off prior chemotherapy, radiation therapy or biologic therapy for at least 3 weeks. mCPRC patients (Cohort 4) may be on hormonal therapy with GnRH agonists/antagonists.

Adults with ECOG performance status 0-2, and adequate organ and marrow function.

Design

Phase I: Durvalumab+O, Durvalumab+C and Durvalumab+O+C will dose escalate simultaneously. Durvalumab will be administered once every 2 weeks or once every 4 weeks until disease progression. O tablets and C will be given orally on a continuous or intermittent dosing schedule. The DLT period will be one cycle, 28 days. Patients on the 2-week schedule greater than one year will be changed to the 4-week schedule until progression.

Durvalumab+O: Durvalumab (3 mg/kg or 10 mg/kg IV every 2 weeks, or a fixed dose of 1500 mg every 4 weeks) and O tablets (150 mg or 200 mg or 300 mg BID)

Durvalumab+C: Durvalumab (3 mg/kg or 10 mg/kg IV every 2 weeks, or a fixed dose of 1500 mg every 4 weeks) and C (15 mg or 20 mg or 30 mg daily or 5 days/week)

Durvalumab+O+C: Durvalumab (a fixed dose of 1500mg every 4 weeks) with O tablets (200 mg or 300 mg BID) and C (15 mg or 20 mg 5 days/week)

Phase II Cohort 1 OvCa Durvalumab+O arm: Patients will be treated with Durvalumab+O at RP2D (O 300mg tablets bid daily and Durvalumab at 1500 mg IV every 4 weeks).

Phase II Cohort 1 OvCa Durvalumab+C arm: Patients will be treated with Durvalumab+C at RP2D (C 20mg once a day [5 days on/2 days off] and Durvalumab at 1500 mg every 4 weeks).

Phase II Cohort 1 OvCa Durvalumab+O+C arm: Patients with OvCa (Cohort 1) will be treated with RP2D (O tablets 300mg BID, C 20mg once a day [5 days on/2 days off] and Durvalumab at 1500 mg every 4 weeks).

Phase II Cohort 2 NSCLC; Durvalumab+O arm: Patients will be treated with Durvalumab+O at RP2D (O 300mg tablets bid daily and Durvalumab at 1500 mg IV every 4 weeks).

Phase II Cohort 2 NSCLC; Durvalumab+C arm: Patients will be treated with Durvalumab+C at RP2D (C 20mg once a day [5 days on/2 days off] and Durvalumab at 1500 mg every 4 weeks).

Phase II Cohort 3 SCLC; Durvalumab+O arm: Patients will be treated with Durvalumab+O at RP2D (O 300mg tablets bid daily and Durvalumab at 1500 mg IV every 4 weeks).

Phase II Cohort 4 mCRPC; Durvalumab+O arm: Patients will be treated with Durvalumab+O at RP2D (O 300mg tablets bid daily and Durvalumab at 1500 mg IV every 4 weeks).

Phase II Cohort 5 TNBC; Durvalumab+O arm: Patients will be treated with Durvalumab+O at RP2D (O 300mg tablets bid daily and Durvalumab at 1500 mg IV every 4 weeks).

Phase II Cohort 6 CRC; C+Durvalumab arm: Patients in the Cohort 6 will be treated with C 20mg daily alone for 14 days followed by the combination at RP2D (C 20mg once a day [5 days on/2 days off] and Durvalumab at 1500 mg every 4 weeks).

Phase II Correlative studies: Research samples including whole blood, CTCs, cell free DNA and plasma will be obtained at pretreatment, prior to cycle 1 day 15, prior to cycle 3 day 1 and at progression. Mandatory baseline core biopsy and two optional biopsies will be obtained.

Patients will be evaluated for toxicity every 4 weeks by CTCAEv4.0, and for response every two cycles (8 weeks) by RECIST 1.1. Patients with mCRPC (Durvalumab+O Cohort 4) will be evaluated for response initially at 8 weeks then every 12 weeks using RECIST v1.1 criteria as per the Prostate Cancer Clinical Trials Working Group 2 (PCWG2).

Details

Condition	Colorectal Neoplasms, Breast Neoplasms
Treatment	MEDI4736, durvalumab, olaparib, Cediranib
Clinical Study Identifier	NCT02484404
Sponsor	National Cancer Institute (NCI)
Last Modified on	29 August 2023

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Eligibility		Yes	No	Not Sure
Inclusion Criteria
	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
	NYHA Class II or greater heart failure
	requiring concurrent use of drugs or biologics with pro-arrhythmic potential
	If cardiac function assessment is clinically indicated or performed, an LVEF less than
	Hypertensive crisis or hypertensive encephalopathy
	normal per institutional guidelines, or <55%, if threshold for normal is not otherwise
	specified by institutional guidelines
	Unstable angina
	QTc prolongation >470 msec or other significant ECG abnormality noted within 14 days
	of treatment
	Clinically significant peripheral vascular disease or vascular disease, including
	rapidly growing aortic aneurysm or abdominal aortic aneurysm >5 cm or aortic
	dissection
	Eligibility for patients with asymptomatic and a previous diagnosis of immune or
	inflammatory colitis, or patients with chronic diarrhea > 1 month without immune
	Pregnant and breastfeeding women are excluded from this study
	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
	ER/PR/HER2 status needs to be documented either by an outside source or at NCI
	HIV viral load and CD4 count > 150 cells/microL) may be eligible if the PI
	determines no anticipated clinically significant drug-drug interactions
	Patients must have measurable disease as defined by RECIST v1.1
	HBV-or HCV-positive patients are ineligible because of potential reactivation of
	hepatitis virus following steroids
	Patients who have received prior PARPi are ineligible
	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
	Patients must have measurable disease as defined by RECIST v1.1
	other PD1 or PD-L1 inhibitors or an anti-CTLA4 therapy are eligible
	Patients with any other concomitant or prior invasive malignancies are
	ineligible
	Patients who have had prior PARPi are not eligible
	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
	Patients who have had prior treatment with PARPi are not eligible
	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)
	Documentation of germline BRCA1 and BRCA2 mutation (gBRCAm) status will be required
	for eligibility
	Patients must have at least one lesion deemed safe to biopsy and be willing to undergo
	a mandatory baseline biopsy
	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 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 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 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

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Phase I/II Study of the Anti-Programmed Death Ligand-1 Durvalumab 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 Can...