Phase 2 Trial of Olaparib in Patients With Metastatic Urothelial Cancer Harboring DNA Damage Response Gene Alterations
Phase 2 Trial of Olaparib in Patients With Metastatic Urothelial Cancer Harboring DNA Damage Response Gene Alterations
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.
Inclusion Criteria:
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.
ECOG Performance Status of ≤ 1 within 14 days prior to registration. Cisplatin-ineligible chemotherapy-naïve subjects (see inclusion criteria #8) may have an ECOG Performance Status of ≤ 2.
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.
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
Subjects must have progressed despite at least 1 prior line of treatment for metastatic and/or unresectable urothelial cancer. However, cisplatin-ineligible (defined by a calculated creatinine clearance of >30 but < 60 mL/min OR CTCAE v4 Grade ≥ 2 audiometric hearing loss OR CTCAE v4 Grade ≥ 2 peripheral neuropathy OR ECOG PS = 2), and chemotherapy-naïve subjects are also eligible.
Prior cancer treatment (systemic therapy or radiation therapy) must be completed at least 3 weeks prior to registration and the subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to Grade ≤ 1 or baseline.
Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 28 days prior to registration.
Female subjects must be postmenopausal or there must be 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.
Females of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of highly effective methods of contraception from the time of informed consent until 90 days after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method. Males must be willing to abstain from heterosexual activity or to use 2 forms of highly effective methods of contraception from the time of informed consent until 90 days after treatment discontinuation.
As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study
15. All subjects must have adequate archival tissue available prior to registration (i.e., at least 15 unstained slides or paraffin block). Archival tissue should represent invasive or metastatic urothelial cancer with a preference for metastatic tissue if available. Archival tissue should be identified at screening and shipped by C1D1. Subjects without adequate tissue may be considered on a case by case basis after discussion with the sponsor-investigator.
Exclusion Criteria