Patient case: 64-year-old male with bladder cancer; genetic feature: FGFR3 (S249C)

Clinical trial: Carboplatin and Gemcitabine Hydrochloride With or Without ATR Kinase Inhibitor VX-970 in Treating Patients With Recurrent and Metastatic Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Summary: This randomized phase I/II trial studies the side effects and how well carboplatin and gemcitabine hydrochloride with or without ATR kinase inhibitor VX-970 work in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back (recurrent) and has spread to other places in the body (metastatic). Drugs used in chemotherapy, such as carboplatin 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 VX-970 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving carboplatin and gemcitabine with or without ATR kinase inhibitor VX-970 may work better in treating ovarian, primary peritoneal, or fallopian tube cancer.

Detailed description: PRIMARY OBJECTIVES:
  I. Assess safety and tolerability of the combination therapy carboplatin, gemcitabine (gemcitabine hydrochloride) and M6620 (VX-970) (rad3-related [ATR] kinase inhibitor VX-970) in adult women with platinum sensitive recurrent high grade serous or high grade endometrioid ovarian, primary peritoneal or fallopian tube cancer. (Phase I Dose Escalation/Safety Lead-in) II. Determine the dose of the triple therapy to be used in the randomized phase 2 portion of the study. (Phase I Dose Escalation/Safety Lead-in) III. To determine whether the addition of M6620 (VX-970) to carboplatin and gemcitabine increases the confirmed response rate (RR) compared to carboplatin and gemcitabine alone in patients with first or second recurrence of platinum sensitive high grade serous or endometrioid ovarian, primary peritoneal or fallopian tube carcinoma. (Randomized Phase 2)
  SECONDARY OBJECTIVES:
  I. To determine whether the addition of M6620 (VX-970) to carboplatin and gemcitabine increases overall survival (OS) compared to carboplatin and gemcitabine alone in first or second recurrence platinum sensitive disease.
  II. To determine whether the addition of M6620 (VX-970) to carboplatin and gemcitabine increases the PFS when compared to carboplatin/gemcitabine alone in first or second recurrence of platinum sensitive disease.
  III. To describe and compare adverse events between the two groups.
  INTEGRATED CORRELATIVE STUDY OBJECTIVES:
  I. To determine whether increased deoxyribonucleic acid (DNA) damage as assessed by multiplex assay correlates with response to combination therapy with M6620 (VX-970).
  II. To determine whether mutations in homologous recombination repair genes correlate with response to combination therapy with M6620 (VX-970).
  III. Assess a limited pharmacokinetic profile of M6620 (VX-970) and gemcitabine when given in combination with carboplatin.
  IV. To ascertain modulation of ATR autophosphorylation and other pharmacodynamic readouts for ATR inhibition by M6620 (VX-970).
  OUTLINE: This is a phase I, dose-escalation study of gemcitabine hydrochloride and ATR kinase inhibitor VX-970 followed by a phase II study. Patients are randomized to 1 of 2 arms.
  ARM I: Patients receive carboplatin intravenously (IV) over 30 minutes on day 1, gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, and ATR kinase inhibitor VX-970 IV over 60 minutes on days 2 and 9.
  ARM II: Patients receive carboplatin IV over 30 minutes on day 1 and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8.
  In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  After completion of study treatment, patients are followed up for 3 years.

Eligibility: Inclusion Criteria:
  -  Histologically confirmed high grade serous or endometrioid ovarian, peritoneal or fallopian tube malignancy that is metastatic and for which curative measures do not exist; the histology can be confirmed from tissue that was taken at the time of diagnosis; a biopsy at the time of recurrence prior to enrollment on study is not required
  -  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 enrolled in the phase 2 portion of the study will be required to have archival tumor tissue available for analysis and be willing to have a tumor biopsy at baseline (after registration and prior to starting study treatment) and at cycle 1 day 2; patients must have platinum sensitive disease and be in their first or second platinum sensitive recurrence; platinum sensitive disease is defined as recurrence that occurred greater than six months after completion of their last line of platinum based therapy; no non-platinum regimens allowed; prior therapy with PARP inhibitors as well as bevacizumab is allowed
  -  No more than two prior platinum based regimens; one regimen is defined as the interval of treatment from start of platinum based doublet to finish of that treatment course for the initial therapy or for the recurrent disease episode; if the nonplatinum agent is altered due to any reason other than disease progression, it counts as one regimen; for example, if a patient started on carboplatin and paclitaxel but developed a taxol reaction and was switched to carboplatin and Abraxane, this counts as one prior regimen
  -  Children are excluded from this study, but will be eligible for future pediatric trials
  -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  -  Life expectancy of greater than 6 months
  -  Leukocytes >= 3,000/mcL
  -  Absolute neutrophil count (ANC) >= 1,500/mcL
  -  Platelets >= 100,000/mcL
  -  Total bilirubin within normal institutional limits
  -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 × institutional upper limit of normal (ULN)
  -  Creatinine within normal institutional limits OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  -  Negative serum pregnancy test result for females of child bearing potential
  -  Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 6 months after completion of VX-970 administration; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
  -  Ability to understand and the willingness to sign a written informed consent document
  Exclusion Criteria:
  -  Patients with platinum resistant disease or platinum sensitive disease that is past the first or second recurrence
  -  Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier, excluding alopecia; patients with treatment related effects, such as peripheral neuropathy, that are grade 1 or less are eligible
  -  Prior exposure to gemcitabine
  -  Patients who are receiving any other investigational agents
  -  Patients with known brain metastases should be excluded from this clinical trial
  -  History of allergic reactions attributed to compounds of similar chemical or biologic composition to M6620 (VX-970), carboplatin, gemcitabine or to these specific compounds
  -  VX-970 is primarily metabolized by cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4); therefore, concomitant administration with strong inhibitors or inducers of CYP3A4 should be avoided
  -  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 (VX-970); these potential risks also apply to the other agents used in this study, such as carboplatin and gemcitabine
  -  Patients with Li Fraumeni syndrome are excluded from the study

Relevance to patient case: not relevant