AZD6738 and Olaparib in Treating Patients with Recurrent High Grade Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Status: Active

Description

This phase II trial studies how well AZD6738 and olaparib work in treating patients with high grade ovarian, primary peritoneal, or fallopian tube cancer that has come back. AZD6738 and olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a life expectancy of at least 6 months
  • Patients must have high grade serous ovarian, primary peritoneal, and/or fallopian tube cancer histologically or cytologically confirmed at the University of Pennsylvania or Johns Hopkins Hospital (JHH) that is recurrent and for which standard curative measures do not exist or are no longer effective
  • All patients must have at least one lesion deemed safe to biopsy and be willing to undergo mandatory biopsies. Cohorts A & B: 75% will require all biopsies (pre-tumor, on-treatment, progressive disease [PD]). If safe, 25% will require a biopsy only at PD. Cohort C: 100% will require all biopsies (pre-tumor, on-treatment, PD)
  • All patients must have a measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
  • Germline BRCA mutation status: * Cohorts A and B: Patients with unknown BRCA status or negative BRCA germline mutation status will be permitted to enroll in the study. Patients with known BRCA germline mutations will be permitted to enroll up to a maximum of 10 patients per cohort * Cohort C: All patients must have either a germline or somatic BRCA mutation, or other HRD mutation, or tumor is HRD positive
  • Creatinine clearance >= 51 ml/min
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels =< 2.5 x upper limit of normal (ULN) (for subjects with liver metastases, AST or ALT =< 5 x ULN)
  • Total bilirubin < 1.5 x ULN, absent Gilbert’s disease
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
  • Platelet count >= 100 x 10^9/L
  • Hemoglobin >= 10 g/dL (in the absence of transfusion within 28 days prior to dosing)
  • Patients must be at least 2 weeks from previous therapy (chemotherapy, hormonal therapy, and radiation therapy, or investigational agents; 6 weeks for mitomycin C) to initiate screening and 3 weeks from previous therapy to initiate treatment
  • Platinum sensitive (recurrence > 6 months by RECIST 1.1 imaging from last platinum) patients may not have had more than 3 prior therapies. Platinum resistant (recurrence =< 6 months by RECIST 1.1 imaging from last platinum regimen) patients may not have had more than 3 prior therapies since the development of platinum resistance
  • Prior treatment with a PARPi is not permitted for Cohorts A and B. Patients enrolled in Cohort C have acquired resistance to PARPi monotherapy, i.e. initial response to a PARP inhibitor followed by disease progression while on a PARP inhibitor. Patients may have not received chemotherapy in the interval between PARPi monotherapy and enrollment. Cohort C patients must also be platinum sensitive
  • Patients who have had major surgery (as defined by the principal investigator [PI]) must be fully recovered and >= 4 weeks post-operative prior to enrolling on study
  • Patients must be able to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening or otherwise altering the product formulation. They should not have gastrointestinal illnesses that would preclude the absorption of AZD6738 or olaparib, which are oral agents
  • Postmenopausal defined as: * Amenorrhea for 1 year or more following cessation of exogenous hormonal treatments * Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in post-menopausal range for women under 50 * Radiation induced oophorectomy with last menses > 1 year ago * Chemotherapy-induced menopause with > 1 year (yr) interval since last menses * Surgical sterilization (bilateral oophorectomy or hysterectomy)
  • Able to understand and voluntarily sign a written informed consent, and are willing and able to adhere to the protocol requirements
  • Patients with a history of brain metastases diagnosed greater than 1 year prior to study entry may be considered if they received sterilizing therapy to the central nervous system (CNS) (resection or radiation) and have been CNS recurrence-free for the 1-year period

Exclusion Criteria

  • Patients with known brain metastases diagnosed within 1 year will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
  • Patients who have had prior AZD6738 or other cell cycle checkpoint inhibitors such as other ATM or ATR inhibitor, WEE-1 inhibitor or CHK1 (or 1/2) inhibitors
  • Patients with a serious cardiac condition, such as congestive heart failure; New York Heart Association class III/IV heart disease; unstable angina pectoris; myocardial infarction within the last 3 months; valvulopathy that is severe, moderate, or deemed clinically significant; or arrhythmias that are symptomatic or require treatment. Resting electrocardiography (ECG) with corrected QT interval (QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
  • Patients with a systolic blood pressure < 90 mm Hg at two consecutive visits or recurrent symptomatic orthostatic hypotension
  • Lack of recovery of prior adverse events due to prior cancer therapy to grade =< 1 (National Cancer Institute [NCI] CTCAE 5.0; except alopecia). Stable persistent grade 2 peripheral neuropathy may be allowed as determined on a case-by-case basis at the discretion of the PI. Patients with platinum-related hypomagnesemia (on replacement) will be eligible
  • Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, clinically significant gastrointestinal (GI) bleeding or hemoptysis within 28 days prior to the start of the study, or psychiatric illness/social situations that would limit compliance with study requirements
  • Another previous, active or current invasive malignancy within the last 5 years, with the exception of curatively treated stage Ia cervical carcinoma, or resected stage IA, grade 1 endometrial cancer, noninvasive non-melanoma skin cancers, ductal carcinoma in situ (DCIS) of the breast or other solid tumors including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease >= 5 yrs. Patients with localized triple negative breast cancer may be eligible who are disease free at least three years out from treatment
  • Immunocompromised patients or human immunodeficiency virus (HIV)-positive patients on highly active antiretroviral therapy (HAART) due to potential drug interaction
  • Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks
  • Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
  • Patients with myelodysplastic syndrome, acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
  • Major surgery within 4 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
  • Patients with a known hypersensitivity to AZD6738 or olaparib or any of the excipients of the product
  • Platinum refractory (progress in first line platinum therapy) are excluded
  • Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
  • Patients with known active hepatitis (i.e. hepatitis B or C) due to risk of transmitting the infection through blood and other body fluids
  • Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
  • Whole blood transfusions in the last 120 days prior to entry to the study

Locations & Contacts

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: Active
Contact: Stephanie Lorene Wethington
Email: swethington@jhmi.edu

Pennsylvania

Philadelphia
University of Pennsylvania / Abramson Cancer Center
Status: Active
Contact: Fiona Simpkins
Phone: 215-662-3318

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of combination ATR kinase inhibitor AZD6738 (AZD6738) and olaparib in recurrent ovarian cancer patients using Common Terminology Criteria for Adverse Events (CTCAE, version 5.0).

II. To determine the objective response rate (complete response [CR] + partial response [PR]) of the combination of AZD6738 and olaparib in women with recurrent ovarian cancer in distinct platinum-sensitive and platinum-resistant cohorts.

SECONDARY OBJECTIVES:

I. To determine the progression-free survival (PFS) of combination AZD6738 and olaparib.

EXPLORATORY OBJECTIVES:

I. Determine the response rate of AZD6738 and olaparib in a small subset of PARP inhibitor (PARPi) resistant (platinum-sensitive) patients with recurrent ovarian cancer (n=12).

II. To determine genetic, and protein changes in the deoxyribonucleic acid (DNA) damage repair and cell cycle checkpoint pathways in tumor and peripheral blood mononuclear cells (PBMCs) in response to treatment.

III. To explore changes in peripheral immune characteristics before and after therapy.

IV. To study cell-free DNA changes in response to treatment.

V. To investigate a method for predicting homologous recombination deficiency (HRD) in ovarian cancer using a positron emission tomography (PET)-labeled PARPi probe, 18F-fluorthanatrace (FTT) and correlate with response to PARPi +/- ATRi.

OUTLINE:

LEAD-IN: Patients receive olaparib orally (PO) twice daily (BID) for 7 days.

TREATMENT: Patients receive olaparib PO BID on days 1-28 and ATR kinase inhibitor AZD6738 PO once daily (QD) on days 1-7. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-4 months.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
University of Pennsylvania / Abramson Cancer Center

Principal Investigator
Fiona Simpkins

Trial IDs

Primary ID UPCC 15817
Secondary IDs NCI-2018-02375
Clinicaltrials.gov ID NCT03462342