Trial of Olaparib in Patients With Metastatic Urothelial Cancer Harboring DNA Damage Response Gene Alterations

NCT03448718 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: HCRN GU15-262
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 7

Brief Summary

This is a single arm open label multi-institutional phase II trial of olaparib monotherapy in subjects with metastatic urothelial cancer harboring somatic DNA damage response (DDR) alterations. The primary objective of the study is to estimate the objective response rate (per RECIST 1.1) to treatment with olaparib.

Conditions

Metastatic Urothelial Cancer

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR)

  Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. ORR is defined as the proportion of all subjects with confirmed PR or CR according to RECIST 1.1.

  Up to a maximum of 17 months

Secondary Outcomes (1)

• Progression-Free Survival (PFS)

  Time of treatment start until the criteria for disease progression or death. Up to a maximum of 17 months.

Other Outcomes (2)

• Overall Survival (OS)

  Time of treatment start until death or date of last contact, up to a maximum of 23 months.

• Adverse Events

  AE had been recorded from time of signed informed consent until 30 days after discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first, up to a maximum of 18 months.

Study Arms (1)

Olaparib Monotherapy

EXPERIMENTAL

The starting dose of olaparib tablets will be dependent on the subject's calculated creatinine clearance (CrCl). Subjects with a CrCl of ≥ 40 mL/min will start at a dose of olaparib tablets of 300 mg twice a day. Subjects with a CrCl of \> 30 to \< 40 mL/min will start at a dose of olaparib tablets 200 mg twice a day.

Drug: Olaparib

Interventions

Olaparib DRUG

1 cycle = 28 days. Subject's with calculated creatinine clearance (CrCl) of ≥ 40 mL/min will start at a dose of olaparib tablets of 300 mg twice a day. Subjects with a CrCl of \> 30 to \< 40 mL/min will start at a dose of olaparib tablets 200 mg twice a day.

Also known as: Lynparza

Olaparib Monotherapy

Eligibility Criteria

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

You may qualify if:

• Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Age ≥ 18 years at the time of consent.
• Histological or cytological evidence/confirmation of urothelial cancer.
• Metastatic and/or unresectable (cT4b) urothelial cancer.
• Metastatic disease evaluable on imaging studies. Subjects may have measurable disease according to RECIST 1.1 or bone-only disease within 30 days prior to registration.
• NOTE: Bone-only subjects are eligible if their disease can be documented/ evaluated by bone scans, CT or MRI. Their disease will be assessed using MD Anderson criteria.34
• NOTE: Previously irradiated lesions are eligible as a target lesion only if there is documented progression of the lesion after irradiation.
• Somatic alteration considered pathogenic/likely pathogenic in one of the following DDR genes as determined by genomic sequencing performed in a Clinical Laboratory Improvement Amendments (CLIA) laboratory. Somatic alterations will include nonsense, frameshift, splice-site or missense mutations or homozygous deletions. Subjects with alterations in DDR genes not included in the list below will be considered on a case by case basis after discussion with the sponsor-investigator(s). Subjects with germline alterations in DDR genes will be considered on a case by case basis and will be reviewed by the sponsor-investigator(s). At least 6 subjects will have BRCA or ATM alterations.
• Nucleotide Excision Repair: ERCC2, ERCC3,ERCC4, ERCC5, ERCC6
• Homologous Recombination: BRCA1, RAD52, BRCA2, RAD54L, RAD50, NBN RAD51, MRE11A, RAD51B, RAD51D, RAD51C, CTIP
• DNA Sensor: ATM, ATR, MDC1, ATRX, CHEK1, CHEK2
• Fanconi Anemia Pathway: PALB2, FANCE, BRIP1, FANCF, FANCA, FANCG FANCB, BLM, FANCC, FANCD2
• Base Excision Repair: XRCC2, XRCC3, XRCC4, XRCC5, XRCC6
• Other: MUTYH, RECQL4, POLQ, POLE, WRN
• A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to study registration, have been off of corticosteroids for ≥ 2 weeks, and are asymptomatic

You may not qualify if:

• Active infection requiring systemic therapy.
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
• Known additional malignancy that is active and/or progressive requiring treatment; subjects with other malignancies that have been definitively treated and who have been rendered disease free will be eligible.
• Prior treatment with a PARP inhibitor, including olaparib.
• Treatment with any investigational drug within 30 days prior to registration.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Resting ECG with QTc \> 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
• Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
• Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
• Subjects with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML.
• Major surgery within 2 weeks of starting study treatment and subjects must have recovered from any effects of any major surgery.
• Subjects 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, history of pneumonitis, or any psychiatric disorder that prohibits obtaining informed consent.
• Subjects unable to swallow orally administered medication and subjects with gastrointestinal disorders likely to interfere with absorption of the study medication.
• Immunocompromised subjects, e.g., subjects who are known to be serologically positive for human immunodeficiency virus (HIV).
• Subjects with a known hypersensitivity to olaparib or any of the excipients of the product.

Sponsors & Collaborators

• Matthew Galsky: lead
• Icahn School of Medicine at Mount Sinai: collaborator
• AstraZeneca: collaborator

Study Sites (7)

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21287, United States

Location

Karmanos Cancer Center (Wyane State University)

Detroit, Michigan, 48201, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029-6542, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Vanderbilt-Ingran Cancer Center

Nashville, Tennessee, 37232, United States

Location

Huntsman Cancer Institute University of Utah

Salt Lake City, Utah, 84112-5550, United States

Location

MeSH Terms

Interventions

olaparib

Results Point of Contact

• Title: Fauzia Sharmin
• Organization: Hoosier Cancer Research Network

fsharmin@hoosiercancer.org

317-921-2050

Study Officials

• Matthew Galsky, MD

  Mt Sinai School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor Investigator

Study Record Dates

• First Submitted: February 22, 2018
• First Posted: February 28, 2018
• Study Start: April 17, 2018
• Primary Completion: July 14, 2021
• Study Completion: October 15, 2021
• Last Updated: November 22, 2023
• Results First Posted: November 22, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)