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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

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ClinicalTrials.gov Identifier: NCT04197713
Recruitment Status : Recruiting
First Posted : December 13, 2019
Last Update Posted : December 1, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

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.

Condition or disease Intervention/treatment Phase
Advanced Malignant Solid Neoplasm Metastatic Malignant Solid Neoplasm Refractory Malignant Solid Neoplasm Unresectable Malignant Solid Neoplasm Drug: Adavosertib Drug: Olaparib Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of olaparib in sequential treatment with adavosertib (AZD1775).

II. To establish the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of this sequential schedule in patients with advanced solid tumors in a post-poly adenosine diphosphate (ADP) ribose polymerase inhibitor (PARPi) population.

III. To assess the safety and toxicity profile of the sequential treatment of olaparib and AZD1775 in a post-PARPi population.

SECONDARY OBJECTIVES:

I. To assess putative predictive biomarkers of response and resistance to the sequential treatment of olaparib and AZD1775 in a post-PARPi population.

II. To evaluate a novel experimental trial design involving sequential dosing of olaparib and AZD1775 in a post-PARPi population.

III. To observe and record anti-tumor activity.

OUTLINE: This is a dose-escalation study of adavosertib.

Patients receive olaparib orally (PO) twice daily (BID) on days 1-5 and 15-19 of each cycle and adavosertib PO once daily (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.

After completion of study treatment, patients are followed up at 30 days and then every 3-6 months for up to 2 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 54 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Sequential Trial of Agents Against DNA Repair (STAR)
Actual Study Start Date : April 15, 2020
Estimated Primary Completion Date : June 30, 2022
Estimated Study Completion Date : June 30, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Olaparib

Arm Intervention/treatment
Experimental: Treatment (olaparib, adavosertib)
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
Given PO
Other Names:
  • AZD-1775
  • AZD1775
  • MK-1775
  • MK1775

Drug: Olaparib
Given PO
Other Names:
  • AZD 2281
  • AZD-2281
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281




Primary Outcome Measures :
  1. Incidence and severity of dose-limiting toxicities [ Time Frame: Up to 28 days ]
  2. Incidence of adverse events [ Time Frame: Up to 30 after administration of last dose of study drug ]
    Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.


Secondary Outcome Measures :
  1. Anti-tumor activity [ Time Frame: Up to 2 years ]
    Will correlate antitumor activity of the sequentially-administered combination of olaparib and adavosertib (AZD1775) with the detection of putative predictive biomarkers of response and resistance.

  2. Maximum tolerated dose (MTD) [ Time Frame: Up to 2 years ]
    Will assess if an MTD can be safely established using sequentially administered combination olaparib and AZD1775.

  3. Overall response rate (ORR) ( complete response [CR] + partial response [PR]) [ Time Frame: Up to 2 years ]
    We will estimate ORR with 95% confidence intervals (CI). Inferences and estimation are based on the exact binomial test.

  4. Duration of response (DOR) [ Time Frame: From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 2 years ]
    Will use the Kaplan-Meier method to estimate DOR in these distributions.

  5. Progression-free survival (PFS) [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years ]
    Will use the Kaplan-Meier method to estimate PFS in these distributions.

  6. Overall survival (OS) [ Time Frame: From start of treatment to time of death, assessed up to 2 years ]
    Will use the Kaplan-Meier method to estimate OS in these distributions.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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, ATM, 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 measureable 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
    • They must have an undetectable viral load and a CD4 count >= 250 cells/uL within 7 days of enrollment
    • They must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months. Monitoring for HIV-infected patients should include:

      • Viral load and CD4 count every 12 weeks (q12w)
      • If CD4 count drops to less than 200 cells/ul while on study, initiate viral load test. If viral load proves undetectable at this time, continue CD4 and viral load checks every 8 weeks (q8w). If 2 consecutive viral load tests are undetectable, revert to q12w testing for CD4 and viral load testing
      • If an opportunistic infection occurs with a CD4 count of < 200 cells/ul, hold study treatment. Initiate treatment of the infection and continue to hold study treatment; once clinically stable, CD4 count is > 200 cells/ul and viral load has remained undetectable, reinitiate study treatment
  • Patients with a past or resolved hepatitis B virus (HBV) infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible. Active HBV is defined by a known positive HBV surface antigen (HBsAg) result. Patients positive for hepatitis C virus (HBC) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. Patients with known active HBV or HBC infection are ineligible
  • Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression within 28 days
  • Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy
  • Absolute neutrophil count (ANC) >= 1500/uL (within 7 days of study drugs initiation)
  • Hemoglobin (Hgb) >= 10 g/dL (within 7 days of study drugs initiation) with no blood transfusion in the past 28 days
  • Platelets >= 100,000/uL (within 7 days of study drugs initiation)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 X upper limit of normal (ULN) (within 7 days of study drugs initiation), unless liver metastases are present in which case they must be =< 5 X ULN
  • Serum bilirubin within normal limits (WNL) (within 7 days of study drugs initiation) or =< 1.5 X ULN in patients with liver metastases, or total bilirubin =< 3 X ULN with direct bilirubin WNL in patients with well-documented Gilbert's syndrome
  • Serum creatinine =< 1.5 X ULN (within 7 days of study drugs initiation). If elevated, check creatinine clearance (CrCl) with cut off >= 51 mL/min as calculated by the Cockcroft-Gault method or based on a 24-hour urine test (confirmation of creatinine clearance is only required when serum creatinine is > 1.5 X institutional ULN)
  • The effects of AZD1775 and olaparib on the developing human fetus are either unclear or are known to be teratogenic, women of childbearing potential and their partners, who are sexually active, must agree to the use of TWO highly effective forms of contraception in combination. This should be started from the signing of the informed consent and continue throughout the period of taking study treatment and for at least 1 month after last dose of study drug(s), or they must totally/truly abstain from any form of sexual intercourse. Male patients must use a condom during treatment and for 3 months after the last dose of study drug when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential. Male patients should not donate sperm throughout the period of taking study drugs and for 3 months following the last dose of study drugs.

    • Acceptable non-hormonal birth control methods include:

      • Total/True abstinence: When the patient refrains from any form of sexual intercourse and this is in line with their usual and/or preferred lifestyle; this must continue for the total duration of the trial and for at least 1 month after the last dose of study drug for women of child bearing potential. For male patients, 3 months after last dose. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods, or declaration of abstinence solely for the duration of a trial] and withdrawal are not acceptable methods of contraception.)
      • Vasectomized sexual partner PLUS male condom. With participant assurance that partner received post-vasectomy confirmation of azoospermia
      • Tubal occlusion PLUS male condom
      • Intrauterine device (IUD) PLUS male condom. Provided coils are copper-banded
    • Acceptable hormonal methods:

      • Normal and low dose combined oral pills PLUS male condom
      • Cerazette (desogestrel) PLUS male condom. Cerazette is currently the only highly efficacious progesterone based pill
      • Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom
      • Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom
      • Norelgestromin / ethinyl estradiol (EE) transdermal system PLUS male condom
      • Intrauterine system (IUS) device (e.g., levonorgestrel releasing IUD-Mirena) PLUS male condom
      • Intravaginal device (e.g., EE and etonogestrel) PLUS male condom
      • In the case of use of oral contraception, women should be stable on the same pill before taking study treatment
      • Note: oral contraceptives are allowed but should be used in conjunction with a barrier method of contraception due to unknown effect of drug-drug interaction. Women are considered post-menopausal and not of childbearing potential if they have had 12 or more months of natural (spontaneous) amenorrhea following cessation of exogenous hormonal treatment with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy). In the case of oophorectomy alone, she will be considered not of childbearing potential only when her reproductive status has been confirmed by follow up hormone level assessment
  • Male patients will be advised to arrange for the freezing of sperm samples prior to the start of the study should they wish to father children while on study drugs or during the 3 months after stopping study drugs
  • Male or female patient >= 18 years of age. Because no dosing or adverse event data are currently available on the use of AZD1775 in combination with olaparib in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1 (Karnofsky >= 70%)
  • Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible. Has read and understands the informed consent form (ICF) and has given written informed consent (IC) prior to any study procedures
  • Willingness and ability to comply with study and follow-up procedures

Exclusion Criteria:

  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD1775 or olaparib
  • Use of an investigational drug during the past 28 days or 5 half-lives (whichever is longer) prior to the first dose of study treatment
  • 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 and excluded because olaparib and AZD1775 are agents with the potential to induce anemia
  • 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])
    • Conduction abnormality not controlled with pacemaker or medication
    • Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
  • Participants with a mean resting corrected QT interval (QTc) >= 480 msec at study entry, as calculated by the Frederica formula (QTcF) by institutional standards obtained from an electrocardiogram (ECG) or congenital long QT syndrome. (Note: if one ECG demonstrates a QTcF > 480 msec, then a mean QTcF of =< 480 msec obtained from 3 ECGs 2-5 minutes apart is required at study entry
  • 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, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04197713


Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Site Public Contact    877-632-6789    askmdanderson@mdanderson.org   
Principal Investigator: Timothy A. Yap         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Timothy A Yap University of Texas MD Anderson Cancer Center LAO
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04197713    
Other Study ID Numbers: NCI-2019-08262
NCI-2019-08262 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10329 ( Other Identifier: University of Texas MD Anderson Cancer Center LAO )
10329 ( Other Identifier: CTEP )
UM1CA186688 ( U.S. NIH Grant/Contract )
First Posted: December 13, 2019    Key Record Dates
Last Update Posted: December 1, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page."
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Olaparib
Poly(ADP-ribose) Polymerase Inhibitors
MK-1775
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents