Protocol No.: OCR31222
Sponsor Protocol No.: 10222
Protocol Title.: Testing Olaparib and AZD6738 in IDH1 and IDH2 Mutant Tumors
Principal Investigator: George, Thomas
Objective: This phase II trial studies how well olaparib and ceralasertib (AZD6738) work in treating patients with IDH mutant cholangiocarcinoma or solid tumors. Cancer is caused by changes (mutations) to genes that control the way cells function. Laboratory studies have shown that olaparib and AZD6738 can shrink IDH mutant tumors or stop them from growing. Olaparib and ceralasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Description: PRIMARY OBJECTIVE: I. To determine the overall response rates of olaparib and ceralasertib (AZD6738) in subjects with recurrent/progressive IDH1/2-mutant solid malignant tumors, who will be recruited to 2 cohorts: a. Cholangiocarcinoma b. Other solid malignant tumors. SECONDARY OBJECTIVES: I. To assess the progression free survival (PFS) of olaparib and AZD6738 in adults with recurrent/progressive IDH1/2-mutant solid malignant tumors. II. To estimate the overall survival (OS) in adults with recurrent/progressive IDH1/2- mutant solid malignant tumors. III. To assess the duration of response in adults with recurrent/progressive IDH1/2-mutant solid malignant tumors. IV. To assess the safety and tolerability of the combination of olaparib and AZD6738. EXPLORATORY OBJECTIVES: I. To evaluate 2-hydroxyglutarate (2HG) concentration in plasma by mass spectrometry and correlate with treatment response. II. To evaluate 2HG levels in tumor biopsies prior to the beginning of treatment and while on therapy and correlate with treatment response. III. Correlate 2HG concentration in plasma and in tumor biopsies. IV. To evaluate deoxyribonucleic acid (DNA) double strand breaks (DSBs) as measured by mass cytometry time of flight (CyTOF)-imaging mass cytometry (IMC) in tumor biopsies before and after treatment with olaparib and AZD6738. OUTLINE: Patients receive olaparib orally (PO) twice daily (BID) on days 1-28 and ceralasertib PO once daily (QD) on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.
Phase: Phase II
Age Group: Adult
Age: 18 Years - N/A
Experimental: Treatment (olaparib, ceralasertib)Patients receive olaparib PO BID on days 1-28 and ceralasertib PO QD on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Detailed Eligibility: Inclusion Criteria: - Subjects must be able to understand the nature of this trial and provide written informed consent, prior to any study specific procedures. Patients with impaired decision making capacity (IDMC) who have a close caregiver or legally authorized representative (LAR) may be considered eligible for this study at the treating physician's discretion, provided that the physician is reasonably sure that the possible risks and benefits of the study are clear and that the patient will take the drug as prescribed - Subjects must be diagnosed with a cholangiocarcinoma or other solid malignant tumor that has progressed despite standard therapy, or for which no effective standard therapy exists. Patients with primary central nervous system (CNS) tumors, e.g. glioma, are not allowed - Patients must have biopsy-confirmed evidence of an IDH1 or IDH2 mutation, confirmed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory, associated with neomorphic activity of the encoded proteins - Patients must have tumors determined to be easily accessible for biopsy and must be willing to have serial biopsies. Tumor biopsies will be performed on the most accessible biopsiable site of disease. All possible precautions to avoid complications will be taken, including discussions in multidisciplinary meetings, if needed. If a patient opts out of a pre-treatment biopsy, biopsy is not possible, or if a pre-treatment biopsy does not yield sufficient tissue for analysis, the patient must be willing to provide an archival formalin-fixed paraffin-embedded (FFPE) specimen, if available, for liquid chromatography/mass spectrometry (LC/MS) analysis of 2HG. Permission of the study principal investigator (PI) is required in all of the above scenarios - In order to maximize the availability of newly obtained specimens for 2-HG analysis, at least 10 biopsies will be required in each group (cholangiocarcinoma and other solid tumors) of 14 patients treated in the first stage of this Simon two-stage design. Thus if 4 patients in an arm have already opted out, further patients may only enroll on that arm (in the first stage) if they agree to undergo the pre- and on-treatment biopsies. If a patient has agreed to undergo the two biopsies and undergoes the pre-treatment biopsy, he or she may not opt out of the second biopsy unless such a biopsy would not be safe (e.g. inaccessible tumor). Permission of the study PI is required in this scenario - All patients must be willing to provide 5 unstained archival slides, if available, for pre-treatment 2-HG analysis and correlation with 2-HG levels in pre-treatment frozen specimens - Patients must be willing to undergo extra blood sampling for correlative studies - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 - Patients must have at least one lesion, not previously irradiated, that can be accurately measured at baseline as >= 10 mm in the longest diameter (except lymph nodes which must have short axis >= 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) or >= 10 mm with callipers by clinical exam OR at least one lesion (measurable and/or non-measurable) that can be accurately assessed by CT/MRI/clinical exam at baseline and follow up visits - Subjects must have progressive cancer at the time of study entry - Prior experimental (non-Food and Drug Administration [FDA] approved) therapies (other than drugs that target ATR) and immunotherapies are allowed. Patients must not have received these therapies for 30 days or five half lives of the drug (whichever is less) prior to the initiation of study treatment - Toxicities from prior therapies should have recovered to == 70%) - Hemoglobin >= 10.0 g/dL with no blood transfusion in = 3,000/mcL (measured within 14 days prior to administration of study treatment) - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (measured within 14 days prior to administration of study treatment) - Platelet count >= 100 x 10^9/L (measured within 14 days prior to administration of study treatment) - Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (measured within 14 days prior to administration of study treatment) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be == 51 mL/min or based on a 24 hour urine test (measured within 14 days prior to administration of study treatment) - No features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) on peripheral blood smear when performed as clinically indicated - Patients must have a life expectancy of >= 16 weeks, in the opinion of the treating physician - Patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up - Prior radiation therapy is allowed. Patients must not have received radiation therapy within 3 weeks prior to the initiation of study treatment - Women of child-bearing potential are expected to use highly effective contraception during the study and for 6 months after the last dose of study drug. Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1 - Postmenopausal is defined as: - Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments - Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post-menopausal range for women under 50 - Radiation-induced oophorectomy with last menses > 1 year ago - Chemotherapy-induced menopause with > 1 year interval since last menses - Surgical sterilization (bilateral oophorectomy or hysterectomy) - Male patients and their partners, who are sexually active and of childbearing potential, must agree to the use of two highly effective forms of contraception in combination, throughout the period of taking study treatment and for 6 months after last dose of study drug(s) to prevent pregnancy in a partner - Patients with human immunodeficiency virus (HIV) on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial Exclusion Criteria: - Involvement in the planning and/or conduct of the study - Previous enrollment in the present study - Participation in another clinical study with an investigational product during the last 30 days or five half-lives of the drug (whichever is less) prior to the initiation of study treatment - Any previous treatment with a PARP inhibitor - Any previous treatment with AZD6738 or any other ATR inhibitor - Patients receiving any systemic chemotherapy or radiotherapy within 3 weeks prior to study treatment - Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1 endometrial carcinoma, or other solid tumors including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for >= 5 years. Patients with a history of localized triple negative breast cancer may be eligible, provided they completed their adjuvant chemotherapy more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease - Resting electrocardiography (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, Fridericia's corrected QT [QTcF] prolongation > 500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome - 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 study treatment 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 study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents - Persistent toxicities caused by previous cancer therapy. Toxicities should have recovered to = 500 mL, and require an overnight hospital stay. Examples include laparoscopic surgery, open resection of organs, joint replacements and other orthopedic surgeries, and vascular or intracranial surgeries. Examples of minor surgeries include those performed on an ambulatory basis, cataract surgery, dental surgeries, cutaneous, endoscopic, and arthroscopic procedures. Effects from major surgeries should have recovered to = 10 mg prednisone/day or equivalent) for any reason - Any of the following cardiac diseases currently or within the last 6 months (by New York Heart Association (NYHA) >= class 2 where applicable): - Unstable angina pectoris - Congestive heart failure or known reduced left ventricular ejection fraction (LVEF) < 55% - Acute myocardial infarction - Conduction abnormality not controlled with pacemaker or medication e.g. complete left bundle branch block, third degree heart block - Significant ventricular or supraventricular arrhythmias e.g. (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible) - Patients at risk of brain perfusion problems, e.g., medical history of carotid stenosis or pre-syncopal or syncopal episodes, history of transient ischemic attacks (TIAs) - Uncontrolled hypertension (grade 2 or above) requiring clinical intervention - Any factors that increase the risk of corrected QT (QTc) prolongation or risk of arrhythmic events such as congestive heart failure, unstable angina pectoris, acute myocardial infarction,