Patient case: 58-year-old female with endometrial cancer; genetic feature: PIK3R1

Clinical trial: Cisplatin and Gemcitabine Hydrochloride With or Without ATR Kinase Inhibitor M6620 in Treating Patients With Metastatic Urothelial Cancer

Summary: This randomized phase II trial studies how well cisplatin and gemcitabine hydrochloride with or without ATR kinase inhibitor M6620 works in treating patients with urothelial cancer that has spread to other places in the body. Drugs used in chemotherapy, such as cisplatin and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. ATR kinase inhibitor M6620 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known if cisplatin and gemcitabine hydrochloride work better alone or with ATR kinase inhibitor M6620 in treating patients with urothelial cancer.

Detailed description: PRIMARY OBJECTIVES:
  I. To determine if the addition of ATR kinase inhibitor M6620 (M6620 [VX-970]) to cisplatin/gemcitabine hydrochloride (gemcitabine) improves progression-free survival (PFS) relative to cisplatin/gemcitabine alone.
  SECONDARY OBJECTIVES:
  I. To compare overall survival (OS) with the addition of M6620 (VX-970) to cisplatin/gemcitabine relative to cisplatin/gemcitabine alone.
  II. To compare tumor response rate with the addition of M6620 (VX-970) to cisplatin/gemcitabine relative to cisplatin/gemcitabine alone.
  III. To compare safety with the addition of M6620 (VX-970) to cisplatin/gemcitabine relative to cisplatin/gemcitabine alone.
  IV. To assess the role of p53 status in predicting response to M6620 (VX-970)-based therapy.
  OUTLINE: Patients are randomized to 1 of 2 arms.
  ARM A: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8, and cisplatin IV over 60 minutes on day 1. Patients also receive ATR kinase inhibitor M6620 IV over 60 minutes on days 2 and 9. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
  ARM B: Patients receive gemcitabine hydrochloride and cisplatin as in Arm A.
  After completion of study treatment, patients are followed up to 36 months.

Eligibility: Inclusion Criteria:
  -  Patients must have histologically or cytologically confirmed metastatic urothelial carcinoma; urothelial cancer derived from the bladder, ureter or upper tract is permitted
  -  Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  -  Patients must have access to archival tumor tissue for proposed correlative studies; these may be derived from transurethral resection of bladder tumors (TURBT), cystectomy, or biopsy; if archival tissue is not available for proposed correlatives, patients may be enrolled at the discretion of the study principal investigator (PI) (SKP)
  -  No prior cytotoxic chemotherapy for metastatic disease; prior immunotherapy is permitted
  -  At least 12 months have elapsed since platinum-based peri-operative treatment
  -  Karnofsky >= 70% (Eastern Cooperative Oncology Group [ECOG] performance status 0-1)
  -  Life expectancy of greater than 3 months
  -  Leukocytes >= 3,000/mcL
  -  Absolute neutrophil count >= 1,500/mcL
  -  Platelets >= 100,000/mcL
  -  Total bilirubin within institutional upper limit of normal
  -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
  -  Creatinine clearance >= 50 mL/min by either measured (using the Cockcroft-Gault, Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology [CKD-EPI] formula) or calculated clearance (i.e. glomerular filtration rate [GFR])
  -  Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of M6620 (VX-970) administration
  -  Ability to understand and the willingness to sign a written informed consent document
  Exclusion Criteria:
  -  Radiotherapy within 4 weeks of protocol therapy
  -  Patients who are receiving any other investigational agents
  -  History of allergic reactions attributed to compounds of similar chemical or biologic composition to M6620 (VX970), cisplatin, or gemcitabine
  -  Concomitant administration with strong inhibitors or inducers of CYP3A4 should be avoided; it is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or minimize use of
  -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  -  Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with M6620 (VX970); these potential risks may also apply to other agents used in this study
  -  Patients with >= grade 2 neuropathy

Relevance to patient case: not relevant