Olaparib with and without AZD1775, AZD5363, and AZD2014 in Treating Patients with Advanced Solid Tumors

Status: Active

Description

This phase II trial studies how well olaparib works with and without other targeted therapies in treating patients with solid tumors that have spread to other places in the body. Olaparib, WEE1 inhibitor AZD1775 (AZD1775), Akt serine / threonine-specific protein kinase (Akt) inhibitor AZD5363 (AZD5363), and mammalian target of rapamycin (mTor) kinase inhibitor AZD2014 (AZD2014) may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and repair. It is not yet known if giving olaparib alone or in combination with AZD1775, AZD5363, or AZD2014 will work better in treating patients with solid tumors that have spread to other places in the body.

Eligibility Criteria

Inclusion Criteria

  • Histologically documented metastatic cancer (solid tumors, not including hematologic malignancies)
  • Patients who have received standard first-line therapy for metastatic cancer (except for the tumors for which no first-line therapy exists) and in whom a trial of targeted therapy is considered the best available treatment option; eligible patients should not have available therapies that will convey clinical benefit
  • Progressive cancer at the time of study entry
  • Measurable disease by RECIST v1.1
  • Life expectancy >= 16 weeks
  • Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1
  • Able to understand the nature of this trial and provide written informed consent
  • Patient is 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
  • Molecular testing results from Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories used for patient eligibility should be obtained from the most recent tumor biopsy (baseline tumor biopsies and on-progression tumor biopsies are optional)
  • No previous treatment with the specific assigned study drug or any other drug sharing the same target; prior treatment in monotherapy when treated in one of the combination arms in the study is allowed
  • Prior radiation therapy is allowed; patients must not have received radiation therapy within 4 weeks prior to the initiation of study treatment
  • Other therapies: Prior experimental (non-Federal Drug Administration [FDA] approved) therapies (other than drugs that share the same target) 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 and must have full recovery from any acute effects of these therapies
  • Absolute neutrophil count (ANC) >= 1500/uL
  • White blood cells (WBC) > 3 x 10^9/L
  • Hemoglobin (Hgb) >= 10 g/dL (may be achieved with erythropoietin agents; no blood transfusions in the 28 days prior to entry)
  • Platelets >= 100,000/uL
  • No features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) on peripheral blood smear
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 × the upper limit of normal (ULN) (=< 5 × ULN if considered due to primary or metastatic liver involvement)
  • Total bilirubin =< 1.5 × ULN
  • Alkaline phosphatase =< 2 × ULN (=< 5 × ULN if considered due to tumor)
  • Serum creatinine =< 1.5 ULN
  • 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 calipers by clinical exam OR at least one lesion (measurable and/or non-measurable) that can be accurately assessed by CT/MRI/plain x-ray/clinical exam at baseline and follow up visits
  • Women of child-bearing potential must have a negative pregnancy test (urine or serum) within 7 days prior to starting the study drug; both males and females must agree to adequate birth control if conception is possible during the study and for 6 months after the last dose; female patients are considered to not be of child-bearing potential if they have a history of tubal ligation or hysterectomy or are post-menopausal with a minimum of 1 year without menses
  • Olaparib * Patients with solid tumors that harbor DNA damage repair gene mutations as exemplified below detected by next-generation sequencing (NGS) or real-time- polymerase chain reaction (RT-PCR) in assays performed at a CLIA-certified laboratory: ** Examples of DNA damage repair deficiency “BRCA-ness” (somatic mutations in tumors), but not limited to, are: breast cancer 1, early onset (BRCA 1), breast cancer 2, early onset (BRCA2)/Fanconi anemia group D1 (FANCD1), partner and localizer of BRCA2 (PALB2 or FANCN), RAD51 recombinase (RAD51), RAD52 homolog, DNA repair protein (RAD52), BRCA1 interacting protein C-terminal helicase 1 gene (FANCJ), Fanconi anemia complementation group D2 (FANCD2), 26S proteasome complex subunit DSS1 (DSS1), MRE11 homolog A, double strand break repair nuclease (MRE11), RAD50 double strand break repair protein (RAD50), nibrin (NBS1), Bloom syndrome RecQ like helicase (BLM), ATM serine/threonine kinase (ATM), ATR serine/threonine kinase (ATR), checkpoint kinase 1 (CHK1), checkpoint kinase 2 (CHK2), Fanconi anemia complementation group (FANC) A,-B,-C, -E, -F, -G,-L, M, D2
  • AZD5363 plus olaparib * Patients with solid tumors with PIK3CA or AKT mutations or other molecular aberrations leading to dysregulation of the PI3K/AKT pathway detected by NGS or RT-PCR in assays performed at a CLIA-certified laboratory: ** activating mutations in PIK3CA, AKT1, AKT2, AKT3, ARID1A ** other molecular aberrations leading to dysregulation of the PI3K/AKT pathway, for example phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) ** during the course of the study new information may emerge relating to molecular aberrations that dysregulate the PI3K/AKT pathway; patients whose tumors bear these aberrations can be included in the study
  • The AZD1775 plus olaparib and AZD2014 plus olaparib additional inclusion criteria will be added as addendums to the protocol and opened once the recommended phase II doses are available

Exclusion Criteria

  • Patients with known germline BRCA mutations will be excluded from the study, however testing is not required for inclusion in the study
  • 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 greater) prior to the initiation of study treatment
  • Prior treatment with the same agent or combination as the study drug; prior treatment in monotherapy when treated in one of the combination arms in the study is allowed
  • Patients with hematologic malignancies (includes patients with myelodysplastic syndrome/acute myeloid leukemia)
  • Patients must not have received allogeneic stem cell transplant
  • Concurrent administration of any other anti-cancer therapy * Bisphosphonates and denosumab for bone metastases are allowed as long as these were started at least 4 weeks prior to treatment with study drug * Octreotide is allowed if dose is stable for > 3 months with no worsening of carcinoid syndrome * Hormonal therapy with luteinizing hormone-releasing hormone (LHRH) analogues for medical castration in patients with castrate-resistant prostate cancer is permitted * Most recent chemotherapy within 3 weeks prior to entering the study * Therapeutic radiotherapy within the previous 3 weeks if =< 5% of their total marrow volume or 4 weeks if > 5% of their total marrow volume, or unresolved acute or subacute toxicities from prior radiotherapy * Most recent experimental (non-FDA approved) anti-cancer therapy or immunotherapies =< 30 days or five half-lives of the drug (whichever is less) * Patients who have not recovered to =< Common Terminology Criteria for Adverse Events (CTCAE) grade 1 toxicities related to prior therapy (administered more than 3 weeks earlier) or incomplete recovery from previous surgery, unless agreed by the principal investigator (PI) and documented are not eligible to participate in this study with the exception of grade 2 peripheral neuropathy if it has been stable, and not worsening, for at least 28 days, and grade 2 alopecia
  • Persistent toxicities (>= CTCAE grade 2) with the exception of alopecia, caused by previous cancer therapy
  • Active or untreated brain metastases or spinal cord compression * A scan to confirm the absence of brain metastases is not required * Patients with treated brain metastases or spinal cord compression are eligible if they have minimal neurologic symptoms and evidence of stable disease (for at least 1 month) or response on follow-up scan; the patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 28 days prior to treatment
  • History of carcinomatous meningitis
  • Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for >= 5 years
  • Patient must not have a co-morbid condition(s) that, in the opinion of the investigator, prevent safe treatment
  • Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy (testing is not part of the protocol)
  • Patients with known (testing is not part of the protocol) active hepatic disease (i.e., hepatitis B or C) due to risk of drug interactions with anti-viral therapy
  • Any of the following cardiovascular events within 6 months prior to study entry: myocardial infarction, malignant hypertension, severe/unstable angina, symptomatic congestive heart failure, cerebral vascular accident, or transient ischemic attack
  • History or presence of clinically significant ventricular or atrial dysrhythmia > grade 2 (National Cancer Institute [NCI] CTCAE version 4.0 [v4.0]) * Patients with chronic, rate-controlled atrial arrhythmias who do not have other cardiac abnormalities are eligible
  • Major surgery within 3 weeks prior to first dose of study treatment, and patients must have recovered from the effects of surgery
  • Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
  • Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease) or significant bowel resection that would preclude adequate absorption
  • Patients with uncontrolled seizures
  • ANC < 1500/ul
  • WBC =< 3 x 10^9/L
  • Platelet count (PLT) < 100,000/ul or
  • Hgb < 10 g/dL
  • Blood (packed red blood cells, platelets) transfusions within 1 month prior to study start
  • Whole blood transfusion in the last 120 days prior to entry to the study
  • Patients with concomitant use of drugs, herbal supplements and/or ingestion of foods known to modulate cytochrome P450 family 3 subfamily A member 4 (CYP3A4) enzyme activity as specified in the drug specific appendix
  • Women who are pregnant or lactating (breastfeeding)
  • Patients with a known hypersensitivity to olaparib or any of the excipients of the product
  • Patients with a known hypersensitivity to the combination/comparator agent
  • Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results * Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection; examples include, but are not limited to, uncontrolled ventricular arrhythmia, superior vena cava syndrome, extensive bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent
  • Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol
  • Olaparib * No additional exclusion criteria
  • AZD5363 plus olaparib * Patients with breast, ovarian and endometrial cancers that carry an AKT1 mutation are excluded from the study due to another ongoing study that enrolls these patients; patients with these tumor types but other mutations can be enrolled in the study * Patients with type I or type II diabetes mellitus; type II diabetes mellitus is allowed if well controlled by dietary measures alone with a glycated hemoglobin (HbgA1c) < 8%; patients found to have a fasting glucose >= 7 mmol/L (126 mg/dL) or HbgA1c > 8% (64 mmol/L) at screening should be assessed for appropriate management according to local policy, of which those in whom dietary measures alone provide good diabetic control (HbgA1c < 8%) will be eligible for inclusion * Patient must have no evidence of troponin elevation (any common toxicity criteria [CTC] grade) * Patient must not have > stage II New York Heart Association (NYHA) classification cardiac status; recent history (i.e., within 6 months) of coronary artery disease or arteriosclerotic cardiovascular disease (angina, myocardial infarction [MI]) * Patient must not have resting left ventricular ejection fraction (LVEF) < 55% measured by multi-gated acquisition (MUGA)/echocardiogram (ECHO) * Patient must not have PR interval greater than 200 msec * Patient must not have clinically significant PR (PQ) interval prolongation * Patient must not have resting LVEF < 55% measured by echocardiogram, regional wall abnormality on ECHO, or any clinically significant structural abnormalities on echocardiogram such as left ventricular hypertrophy or diastolic dysfunction or valvular disease * Patient must not have QTcF > 480 msec or b) family history of long QT Syndrome or c) evidence of recent myocardial infarction e.g. within 6 months prior to start of study treatment) or risk of having a re-infarction, or d) history of torsade de pointes or e) QTcF < 350 msec (short QT syndrome) * Patient must not have intermittent second or third degree atrioventricular (AV) block (second degree AV block [Mobitz Type I and II]; third degree AV block [complete heart block]); incomplete, full or intermittent bundle branch block (QRS 110-120ms with normal QRS and T wave morphology is permitted if there is no evidence of left ventricular hypertrophy); Mobitz type 1, Wenckebach while asleep is permitted * Patient must not have clinically significant abnormalities in T wave or ST-T changes that can be indicative or be suggestive of acute ischemic changes or acute injury pattern * Use of any known potent negative inotropic drug - calcium channel blockers: verapamil, diltiazem; beta-blockers (pending discussion with cardiac SKG): metoprolol, propranolol, atenolol, bisoprolol, carvedilol, timolol, sotalol, esmolol; anti- arrhythmics (class I): disopyramide, procainamide, mexiletine; (class III): amiodarone * Patients with uncontrolled hypotension (systolic blood pressure < 90 mmHg and/or diastolic blood pressure < 50 mmHg) * Patients with potassium or sodium levels outside the normal range for the site * Patients with proteinuria (3+ on dipstick analysis or > 500 mg/24 hours)

Locations & Contacts

Connecticut

New Haven
Yale University
Status: Active
Contact: Joseph Paul Eder
Phone: 203-737-1906
Email: joseph.eder@yale.edu

Massachusetts

Boston
Dana-Farber Cancer Institute
Status: Active
Contact: Geoffrey Ira Shapiro
Phone: 617-632-4942
Email: geoffrey_shapiro@dfci.harvard.edu

Ohio

Cleveland
Cleveland Clinic Cancer Center / Fairview Hospital
Status: Active
Contact: Davendra Pratap Singh Sohal
Email: sohald@ccf.org

Tennessee

Nashville
Vanderbilt University / Ingram Cancer Center
Status: Active
Contact: Vicki L. Keedy
Phone: 615-936-8422
Email: vicki.keedy@vanderbilt.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine tumor overall response rate (ORR) in molecularly selected patients with measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), before versus after 16 weeks of treatment across tumor types in each arm of the study.

SECONDARY OBJECTIVES:

I. To determine tumor clinical benefit rate (CBR) in molecularly selected patients with measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), before versus after 16 weeks of treatment across tumor types and within tumor type in each arm of the study.

II. To determine progression free survival (PFS), duration of overall response, and duration of stable disease in molecularly selected patients with measurable disease as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST), before versus after 16 weeks of treatment across tumor types and within tumor type in each arm of the study.

III. To determine the safety and tolerability of oral administration of olaparib alone and in combination of AZD1775, AZD5363, and AZD2014 in patients with advanced solid tumors.

IV. To collect and store molecular profiling data of all patients enrolled in this study, for the purpose of correlating treatment response/clinical benefit with patterns of tumor genetic abnormalities in tumors.

TERTIARY OBJECTIVES:

I. To correlate clinical benefit rate (CBR) associated with treatment at week 16 (overall response rate (ORR), complete response (CR), and partial response (PR)) with additional defects in deoxyribonucleic acid (DNA) repair pathways as measured by genetic aberrations in the tumors.

II. To compare genetic variants/mutations measured in tumor tissue in diagnostic archival specimen, at baseline and on progression (when samples available), and correlate with tumor response and clinical benefit.

III. To determine tumor mutations in circulating tumor deoxyribonucleic acid (ctDNA) at baseline, on treatment, and at progression, and evaluate the changes in ctDNA mutations and correlate with tumor response and clinical benefit.

OUTLINE: Patients are assigned to 1 of 4 arms.

ARM I: Patients with tumors harboring mutations in DNA damage repair genes receive olaparib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients with tumors harboring phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), AKT, or AT-rich interaction domain 1A (ARID1A) mutations or other molecular aberrations leading to dysregulation of the PI3K/AKT pathway receive olaparib as outlined in arm I. Patients also receive Akt inhibitor AZD5363 PO BID on days 1, 2, 8, 9, 15,16, 22, and 23 at least 1 hour after olaparib. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM III: Patients with tumors harboring tumor protein 53 (TP53) and/or v-Ki-RAS2 kirsten rat sarcoma 2 viral oncogene homolog gene (KRAS) mutations receive olaparib as outlined in arm I. Patients also receive WEE1 inhibitor AZD1775 PO BID on days 1-28 at least 1 hour after olaparib. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM IV: Patients with tumors harboring mutations in raptor-mTOR protein complex (TORC1)/rictor-mTOR protein complex (TORC2), or tuberous sclerosis 1/2 (TSC1/2) or serine/threonine kinase 11 (LKB1), or patients who are phosphatase and tensin homolog (PTEN)-deficient receive olaparib as outlined in arm I. Patients also receive mTor kinase inhibitor AZD2014 PO BID on days 1-28 at least 1 hour after olaparib. Courses 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.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Yale University

Principal Investigator
Joseph Paul Eder

Trial IDs

Primary ID 1508016363
Secondary IDs NCI-2016-00922
Clinicaltrials.gov ID NCT02576444