Clinical Trial 18844

Cancer Type: Multiple
Interventions:AZD2171 (Cediranib); Cediranib (Recentin); Olaparib (Lynparza)

Study Type: Treatment
Phase of Study: Phase II
Investigators:

  • Hatem Soliman

Overview

Study Title

A Phase 2 Study of Cediranib in Combination with Olaparib in Advanced Solid Tumors

Summary

The purpose of this study is to test any good and bad effects of this combination of drugs - cediranib and olaparib. Researchers hope to learn if this combination of the drugs will shrink the cancer by at least one-quarter compared to its present size. Cediranib is an experimental drug. Olaparib has already been FDA-approved to treat patients with advanced ovarian cancer.

Objective

Primary Objectives To determine the objective response rate (ORR) of cediranib plus olaparib in combination in patients with advanced or metastatic solid tumors of the following tumor types: non-small cell lung cancer (NSCLC), germline BRCA1/2wt, basaloid triple negative breast cancer (b-TNBC), pancreatic ductal adenocarcinoma (PDAC), and small cell lung cancer (SCLC). The responses will be assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary Objectives To assess the safety and tolerability of oral administration of cediranib in combination with olaparib in patients with select advanced solid tumors.

Inclusion Criteria

  • Histologically confirmed, metastatic or unresectable malignancy of the following types: (a) non-squamous, non-small cell lung cancer (NSCLC), (b) triple-negative breast cancer (TNBC; defined by estrogen receptor [ER] less than1%, progesterone receptor [PR] less than 1% and human epidermal growth factor receptor 2 f[HER2] immunohistochemistry [IHC]: 1+ or less; if 2+, a negative fluorescence in situ hybridization [FISH] testing is required) without germline BRCA mutation, (c) pancreatic adenocarcinoma (PDAC), or (d) small cell lung cancer (SCLC). NSCLC ONLY:
  • First 20 evaluable participants only: Willing to undergo paired FMISO PET scans; Willing to undergo paired biopsies.
  • Have progressive disease after platinum-based regimen and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor(s) (TKI[s]) or anaplastic lymphoma receptor tyrosine kinase (ALK) inhibitors if sensitizing mutations are present. TNBC ONLY:
  • Must be known germline BRCA wild-type; BRCA mutation carriers are excluded; if unknown, then BRCA testing must be performed in a Clinical Laboratory Improvement Amendments (CLIA) certified lab.
  • Have basaloid subtype TNBC as determined by research PAM-50 test.
  • Have tumor amenable for and be willing to undergo, baseline and on-treatment biopsies (first 20 evaluable participants only).
  • Have received at least 1 prior chemotherapy regimen in the metastatic setting. PDAC ONLY:
  • Have received at least one standard chemotherapy either with or without radiation therapy based on the institution's standard of care. SCLC ONLY:
  • Have had a standard platinum-based regimen for limited or extensive stage disease. ALL PARTICIPANTS:
  • Measurable disease by RECIST v1.1
  • Toxicities of prior therapy (except alopecia) should be resolved to => Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >= 70%)
  • Life expectancy of >= 4 months
  • Adequate hematologic, hepatic, bone marrow and renal function
  • Activated partial thromboplastin time (aPTT) within 1.25 x institutional upper limit of normal (ULN), except where a lupus anti-coagulant has been confirmed
  • Able to tolerate oral medications and not have gastrointestinal illnesses that would preclude absorption of cediranib or olaparib
  • Adequately controlled thyroid function, with no symptoms of thyroid dysfunction and thyroid stimulating hormone (TSH) within normal limits
  • Adequately controlled blood pressure (BP) > Patients with the following risk factors are considered to be at increased risk for cardiac toxicities, and must have documented left ventricular ejection fraction (LVEF) by echocardiogram greater than institution's lower limit of normal (or 55% if threshold for normal not otherwise specified by institutional guidelines) obtained within 3 months: (a) Prior treatment with anthracyclines; (b) Prior treatment with trastuzumab; (c) A New York Heart Association (NYHA) classification of II controlled with treatment; (d) Prior central thoracic radiation therapy (RT), including RT to the heart; (e) History of myocardial infarction within 12 months (patients with history of myocardial infarction within 6 months are excluded from the study).
  • Women of child-bearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation. Men treated or enrolled must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 4 months after completion of cediranib and olaparib administration.

  • Exclusion Criteria

  • Known deleterious BRCA germline mutation by standard clinical testing; for TNBC participants only, BRCA germline testing is required, if not performed previously
  • Have had chemotherapy or RT within 3 weeks prior to start of the study agents, or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier
  • Should not have received any other investigational agents within the past 4 weeks
  • An untreated brain metastases, spinal cord compression, or evidence of symptomatic brain metastases or leptomeningeal disease as noted on computed tomography (CT) or magnetic resonance imaging (MRI) scans; screening Brain MRI will be required for patients with recurrent NSCLC, TNBC, or SCLC; brain MRI is required for PDAC if clinically suspected by patient's symptoms or neurological exam. Should patient found to have brain metastasis, treatment metastasis must precede the participation in this study; for patients with known and treated brain metastases is allowed in this study if they meet specific additional criteria.
  • Have received prior inhibitor of VEGF signaling and a poly (ADP-ribose) polymerases (PARP) inhibitor administered in combination; unless administered in combination
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to cediranib or olaparib
  • Receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; dihydropyridine calcium-channel blockers are permitted for management of hypertension
  • Concomitant or prior invasive malignancies within the past 3 years (Exception: treated limited stage basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the breast or cervix)
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • History of myocardial infarction, stroke or transient ischemic attack within 6 months
  • NYHA classification of III or IV
  • Current condition requiring concurrent use of drugs or biologics with anti-arrhythmic or pro-arrhythmic potential
  • History of hypertensive crisis or hypertensive encephalopathy within 3 years
  • Clinically significant peripheral vascular disease or vascular disease (abdominal aortic aneurysm (> 5 cm) or aortic dissection); if known history of abdominal aortic aneurysm with > 4cm in diameter, specific criteria must be met:
  • A major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to starting cediranib (percutaneous/endobronchial biopsies are allowed)
  • Current signs and/or symptoms of bowel obstruction within 1 month prior to starting study drugs, except if it was a temporary incident (improved within less than 24 hrs with medical management)
  • History of hemoptysis within the last 1 month
  • Presence of cavitation of central pulmonary lesion
  • History of abdominal fistula, intra-abdominal abscess, or gastrointestinal perforation with the 3 months
  • Current dependency on intravenous (IV) hydration or total parenteral nutrition (TPN)
  • Evidence of coagulopathy or bleeding diathesis; therapeutic anticoagulation for prior thromboembolic events is permitted if specific criteria are met
  • Features suggestive of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if clinically indicated
  • Pregnant or breastfeeding
  • Human immunodeficiency virus (HIV)-positive, on combination antiretroviral therapy