Testing the Sequential Combination of the Anti-cancer Drugs Olaparib Followed by Adavosertib (AZD1775) in Patients With Advanced Solid Tumors With Selected Mutations and PARP Resistance, STAR Study

NCT04197713 | Active Not Recruiting Phase 1 Results FDA Drug

• 3 other identifiers: NCI-2019-0826210329UM1CA186688
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial studies the side effects and best dose of adavosertib when given together with olaparib in treating patients with solid tumors that have spread to other places in the body (advanced) with selected mutations. Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Giving olaparib and adavosertib one after the other may shrink or stabilize advanced solid tumors as successfully as using them together, with fewer side effects.

Conditions

Metastatic Malignant Solid Neoplasm; Refractory Malignant Solid Neoplasm; Unresectable Malignant Solid Neoplasm; Advanced Malignant Solid Neoplasm

Outcome Measures

Primary Outcomes (2)

• Dose Limiting Toxicity

  The number of patients who had dose limiting toxicity (DLT). DLT was defined as grade ≥3 non-hematological toxicity, grade 3 fatigue of greater than 1 week duration, failure to receive at least 70% of dosing due to trial drug-related toxicities, or experiencing a drug-related toxicity that meets criteria for a DLT, grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding, grade 4 neutropenia ≥5 days or febrile neutropenia, Any degree of anemia, leukopenia in the absence of grade 4 neutropenia ≥4 days.

  Within the first cycle (28 days) of treatment

• Incidence and Causality of Treatment-Related Adverse Events

  The data represents the number of patients with reported treatment-related adverse events that were deemed at least possibly, probably, or definitely related to study treatment, and were graded based on the Common Terminology Criteria for Adverse Events, Version 5(CTCAE 5.0). Only the highest grade assigned for each treatment-related adverse event is reported.

  Approximately 2 years and 7 months. For each enrolled patient, adverse event data was captured from the period in which a patient signed the informed consent and up to 90 days after the administration of the last dose of study drug.

Secondary Outcomes (5)

• Maximum Tolerated Dose (MTD)

  The MTD will be identified in the dose escalation phase. Once identified, the MTD will be used by the dose expansion cohorts through study completion, which will take place for approximately 2 years after MTD is identified.

• Objective Response Rate

  Tumor reassessment every 8 weeks from start of treatment until radiological documentation of disease progression/recurrence through study completion, for a period of approximately 3 years.

• Clinical Benefit

  Tumor reassessment every 8 weeks from start of treatment until radiological documentation of disease progression/recurrence through study completion, for a period of approximately 3 years.

• Progression-free Survival (PFS)

  From treatment start to progression or death, whichever occurred first or to the last imaging scan.

• Overall Survival (OS)

  Tumor reassessment every 8 weeks from start of treatment until radiological documentation of disease progression/recurrence through study completion, for a period of approximately 3 years.

Study Arms (1)

Treatment (olaparib, adavosertib)

EXPERIMENTAL

Patients receive olaparib PO BID on days 1-5 and 15-19 of each cycle and adavosertib PO QD on days 8-12 and 22-26 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Adavosertib; Drug: Olaparib

Interventions

Adavosertib DRUG

Given PO

Also known as: AZD 1775, AZD-1775, AZD1775, MK 1775, MK-1775, MK1775

Treatment (olaparib, adavosertib)

Olaparib DRUG

Given PO

Also known as: AZD 2281, AZD-2281, AZD2281, KU 0059436, KU-0059436, KU0059436, Lynparza, Olanib, Olaparix, PARP Inhibitor AZD2281

Treatment (olaparib, adavosertib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective
• Patients in dose expansion Cohort A (intrinsic resistance), must have:
• Prior treatment with PARP inhibitors
• Disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) at 1st re-staging, and
• Germline or somatic mutations in BRCA1 or BRCA2
• Patients in dose expansion Cohort B (acquired resistance) must have:
• Prior treatment with PARP inhibitors,
• Complete/partial response followed by disease progression per RECIST, and
• Germline or somatic mutations in any of the following deoxyribonucleic acid (DNA) damage response (DDR) genes: BRCA1, BRCA2, BRIP1, FANCA, PALB2, or the non-DDR gene marker cyclin E amplification. Local testing in Clinical Laboratory Improvement Act (CLIA)-certified laboratory will be accepted. All alterations will be reviewed by MD Anderson's Precision Oncology Decision Support (PODS) team. No variants of uncertain significance (VUS) will be allowed as the qualifying genetic mutation. Recruitment of patients with relevant molecular aberrations in the dose escalation phase is encouraged but not mandated.
• Subjects must have RECIST measurable disease and a tumor that is safely accessible for biopsy and must be willing to undergo biopsy
• Subjects must have received at least one line of systemic therapy in the advanced/metastatic setting. Subjects with diseases without known effective options, and subject who have declined standard or care therapy prior to study introduction are also eligible
• Any prior palliative radiation therapy must have been completed at least 14 days prior to the start of study drugs, and patients must have recovered from any acute adverse effects prior to the start of study treatment
• Human immunodeficiency virus (HIV)-infected (HIV1/2 antibody-positive) patients may participate if they meet all the following eligibility requirements:
• They must be on an anti-retroviral regimen with evidence of at least two undetectable viral loads within the past 6 months on this same regimen; the most recent undetectable viral load must be within the past 12 weeks
• They must have a CD4 count \>= 250 cells/uL over the past 6 months on this same anti-retroviral regimen and must not have had a CD4 count \< 200 cells/ul over the past 2 years, unless it was deemed related to the cancer and/or chemotherapy-induced bone marrow suppression. For patients who have received chemotherapy in the past 6 months, a CD4 count \< 250 cells/ul during chemotherapy is permitted as long as viral loads were undetectable during this same chemotherapy

You may not qualify if:

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD1775 or olaparib
• Use of anti-cancer treatment drug =\< 28 days or 5 half-lives (whichever is shorter) prior to the first dose of study treatment. For drugs for which 5 half-lives is =\< 21 days, a minimum of 10 days between termination of the prior treatment and administration of study treatment is required
• Use of radiotherapy (except for palliative reasons) within =\< 28 days prior to study treatment
• No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal anticancer therapy radiotherapy), biological therapy or other novel agent is to be permitted while the patient is receiving study medication. Patients with castration-resistant prostate cancer on luteinizing hormone-releasing hormone (LHRH) analogue treatment for more than 6 months are allowed entry into the study and may continue at the discretion of the investigator
• Concomitant use of CYP3A inducers/inhibitors:
• 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 study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
• Major surgical procedures =\< 28 days of beginning study treatment, or minor surgical procedures =\< 7 days. Patients must have recovered from any of the effects of any major surgery. No waiting period required following port-a-cath placement or other central venous access placement
• Known malignant central nervous system (CNS) disease other than neurologically stable, treated brain metastases - defined as metastasis having no evidence of progression or hemorrhage for at least 2 weeks after treatment (including brain radiotherapy). Must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to enrollment. Subjects with brain metastases must have completed treatment, either surgery or radiation, and be stable for at least 28 days off steroid prior to screening. A brain magnetic resonance imaging (MRI) demonstrating there is no current evidence or progressive brain metastases is required in subjects with previous brain metastasis. Patients with breast tissue expanders may have brain computed tomography (CT) for assessment
• Patients with either previous or current myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or features suggestive of MDS/AML (e.g., persistent anemia or other blood dyscrasias) are excluded because olaparib and AZD1775 are agents with the potential to induce MDS/AML
• AZD1775 should not be given to patients who have a history of Torsades de pointes (TdP) unless all risk factors that contributed to TdP have been corrected
• Any of the following cardiac diseases currently or within the last 6 months:
• Unstable angina pectoris
• Acute myocardial infarction
• Congestive heart failure \>= class 2 (as defined by New York Heart Association \[NYHA\])

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

adavosertib; olaparib

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Dr. Timothy Yap
• Organization: University of M D Anderson Cancer Center

tyap@mdanderson.org

713) 563-1784

Study Officials

• Timothy A Yap

  University of Texas MD Anderson Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 12, 2019
• First Posted: December 13, 2019
• Study Start: June 30, 2020
• Primary Completion: February 22, 2023
• Study Completion (Estimated): December 31, 2026
• Last Updated: April 29, 2026
• Results First Posted: October 1, 2024

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

US (1)