Clinical Trials /

Gemcitabine Hydrochloride Alone or With M6620 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

NCT02595892

Description:

This randomized phase II trial studies how well ATR kinase inhibitor M6620 (M6620) and gemcitabine hydrochloride work compared to standard treatment with gemcitabine hydrochloride alone in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back after a period of improvement (recurrent). ATR kinase inhibitor M6620 may stop the growth of tumor cells by blocking an enzyme needed for cell growth, and may also help gemcitabine hydrochloride work better. Gemcitabine hydrochloride is a drug used in chemotherapy that works to stop the growth of tumor cells by blocking cells from growing and repairing themselves, causing them to die. It is not yet known whether adding ATR kinase inhibitor M6620 to standard treatment with gemcitabine hydrochloride is more effective than gemcitabine hydrochloride alone in treating patients with ovarian, primary peritoneal, or fallopian tube cancer.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Ovarian Serous Tumor
  • Primary Peritoneal Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Gemcitabine Hydrochloride Alone or With VX-970 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
  • Official Title: Phase 2 Study of VX-970 (NSC# 780162) in Combination With Gemcitabine Versus Gemcitabine Alone in Subjects With Platinum-Resistant Recurrent Ovarian or Primary Peritoneal Fallopian Tube Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-01910
  • SECONDARY ID: NCI-2015-01910
  • SECONDARY ID: 9944
  • SECONDARY ID: 9944
  • SECONDARY ID: P30CA006516
  • SECONDARY ID: UM1CA186709
  • NCT ID: NCT02595892

Conditions

  • Ovarian Serous Tumor
  • Recurrent Fallopian Tube Carcinoma
  • Recurrent Ovarian Carcinoma
  • Recurrent Primary Peritoneal Carcinoma

Interventions

DrugSynonymsArms
ATR Kinase Inhibitor VX-970VX-970Arm II (gemcitabine, ATR kinase inhibitor VX-970)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, Gemzar, LY-188011, LY188011Arm I (gemcitabine hydrochloride)

Purpose

This randomized phase II trial studies how well Ataxia-telangiectasia and Rad3-related [ATR] kinase inhibitor VX-970 (VX-970) and gemcitabine hydrochloride work compared to standard treatment with gemcitabine hydrochloride alone in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back after a period of improvement (recurrent). ATR kinase inhibitor VX-970 may stop the growth of tumor cells by blocking an enzyme needed for cell growth, and may also help gemcitabine hydrochloride work better. Gemcitabine hydrochloride is a drug used in chemotherapy that works to stop the growth of tumor cells by blocking cells from growing and repairing themselves, causing them to die. It is not yet known whether adding ATR kinase inhibitor VX-970 to standard treatment with gemcitabine hydrochloride is more effective than gemcitabine hydrochloride alone in treating patients with ovarian, primary peritoneal, or fallopian tube cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Assess and compare progression free survival (PFS) between gemcitabine (gemcitabine
      hydrochloride)/VX-970 and gemcitabine alone arms.

      SECONDARY OBJECTIVES:

      I. Determine and compare overall response rate (ORR) by Response Evaluation Criteria in
      Solid Tumors (RECIST) between gemcitabine/VX-970 and gemcitabine alone arms.

      II. Determine and compare the safety profile of gemcitabine/VX-970 and gemcitabine alone
      regimens.

      III. Assess and compare PFS at 6 months between gemcitabine/VX-970 and gemcitabine alone
      arms.

      IV. Determine and compare the clinical benefit rate (CBR) between gemcitabine/VX-970 and
      gemcitabine alone arms.

      V. Determine and compare the duration of response (DOR) between gemcitabine/VX-970 and
      gemcitabine alone arms.

      VI. Determine and compare cancer antigen (CA)125 reduction by >= 50% between
      gemcitabine/VX-970 and gemcitabine alone arms.

      VII. Determine and compare overall survival (OS) between gemcitabine/VX-970 and gemcitabine
      alone arms.

      VIII. Determine the ORR for subjects in the gemcitabine alone arm who cross over to the
      gemcitabine/VX-970 arm.

      OUTLINE: Patients are randomized to 1 of 2 treatment arms.

      ARM I: Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days
      1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable
      toxicity. Patients experiencing disease progression may crossover to Arm II.

      ARM II: Patients receive gemcitabine hydrochloride as in Arm I and ATR kinase inhibitor
      VX-970 IV over 60-90 minutes on days 2 and 9. Courses repeat every 21 days in the absence of
      disease progression or unacceptable toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Arm I (gemcitabine hydrochloride)Active ComparatorPatients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm II.
  • Gemcitabine Hydrochloride
Arm II (gemcitabine, ATR kinase inhibitor VX-970)ExperimentalPatients receive gemcitabine hydrochloride as in Arm I and ATR kinase inhibitor VX-970 IV over 60-90 minutes on days 2 and 9. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • ATR Kinase Inhibitor VX-970
  • Gemcitabine Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed high grade serous ovarian or primary
             peritoneal or fallopian tube cancer; platinum resistant disease is defined as
             progression within 6 months after last platinum regimen

          -  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; measurable
             disease by RECIST version (v)1.1 with at least one measurable target lesion

          -  Prior therapy: No line limit but no more than 1 prior regimens in the platinum
             resistant setting; no prior treatment targeting the ATR/checkpoint kinase 1 (CHK1)
             pathway and no prior gemcitabine as single agent; hormonal therapies and
             antiangiogenic therapies (as single agents) do not count as lines; poly (adenosine
             diphosphate [ADP]-ribose) polymerases (PARP)-inhibitors count as line of therapy;
             prior carboplatin/gemcitabine is allowed provided that there was no disease
             progression within 12 months after completion of the carboplatin/gemcitabine regimen;
             subjects may begin protocol treatment at least 4 weeks or 5 half-lives, whichever is
             shorter, after their last dose of chemotherapy or hormonal therapy, assuming they are
             otherwise eligible

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >=
             70%)

          -  Life expectancy of greater than 6 months

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 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])
             =< 2.5 × institutional upper limit of normal

          -  Creatinine within normal institutional limits OR creatinine clearance >= 60
             mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

          -  Confirmation of availability of a formalin-fixed, paraffin-embedded (FFPE) tumor
             specimen with adequate tumor tissue (either one paraffin embedded tissue block OR 10
             5-micron unstained slides from the block on regular (non-plus) slides and 1
             hematoxylin and eosin [H&E] slide)

          -  All acute, clinically significant treatment-related toxicity from prior therapy,
             except for alopecia, must have resolved to grade =< 1 prior to study entry

          -  Patients with symptomatic uncontrolled brain metastases are excluded; a scan to
             confirm the absence of brain metastases is not required

          -  At least 4 weeks since major surgery or radiation therapy

          -  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 study; 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

          -  No known hypersensitivity or contraindication to the components of study treatment
             (VX-970, gemcitabine)

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Patients with primary platinum refractory disease, defined as progression while first
             line platinum based chemotherapy

          -  Patients who have had chemotherapy within 4 weeks or five half-lives, whichever is
             shorter, (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or
             those who have not recovered from adverse events due to agents administered more than
             4 weeks earlier

          -  Patients who have had radiotherapy within 4 weeks

          -  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 VX-970 or gemcitabine

          -  Concomitant administration with strong inhibitors or inducers of cytochrome P450,
             family 3, subfamily A, polypeptide 4 (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; patients receiving any medications or substances that are
             inhibitors or inducers of cytochrome P450 3A (CYP3A4 enzyme) are ineligible; as part
             of the enrollment/informed consent procedures, the patient will be counseled on the
             risk of interactions with other agents, and what to do if new medications need to be
             prescribed or if the patient is considering a new over-the-counter medicine or herbal
             product

          -  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 VX-970 and/or gemcitabine

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy are ineligible; appropriate studies will be undertaken in patients receiving
             combination antiretroviral therapy when indicated
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:PFS
Time Frame:Number of days from the day the subject received the first dose of protocol therapy to the date of documented progressive disease by RECIST version 1.1 or death (regardless of cause), assessed up to 3 years
Safety Issue:
Description:PFS will be summarized using Kaplan-Meier analyses and compared between the two arms using the logrank test. PFS will additionally be analyzed using a Cox Proportional Hazards Model, including the stratification factor, and will be used to estimate the hazard ratio of the gemcitabine hydrochloride/ATR kinase inhibitor VX-970 arm relative to the gemcitabine hydrochloride alone arm and the associated 90% confidence interval.

Secondary Outcome Measures

Measure:CBR, defined as the percentage of subjects achieving a response rating of stable disease >= 4 months, PR, or CR
Time Frame:Up to 3 years
Safety Issue:
Description:Subject demographic and baseline characteristics will be summarized by mean, standard deviation, median, minimum, and maximum for continuous variables; and by counts and percentages for categorical variables. Summaries will be provided separately for each treatment group. Treatment group comparisons in CBR will be evaluated using logistic regression and expressed as odds ratios with associated 90% confidence intervals. In the event that rates are low, comparisons will be based on Fisher's exact test.
Measure:Change in CA125 serum levels
Time Frame:Baseline to up to 30 days after last dose of study treatment
Safety Issue:
Description:Subject demographic and baseline characteristics will be summarized by mean, standard deviation, median, minimum, and maximum for continuous variables; and by counts and percentages for categorical variables. Summaries will be provided separately for each treatment group. Percent of subjects with at least 50% reduction in CA-125 will be evaluated and presented with 95% confidence intervals and compared across the two groups using z-test for independent proportions. Treatment group comparisons in CA-125 50% reduction will be evaluated using logistic regression and expressed as odds ratios with
Measure:Duration of response
Time Frame:Up to 3 years
Safety Issue:
Description:Informational summaries and Kaplan Meier plots, without formal statistical comparisons, will be produced.
Measure:Incidence of toxicity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
Time Frame:Up to 30 days after last dose of study treatment
Safety Issue:
Description:The following minimum data summaries will be presented by treatment arm for safety assessments: treatment-emergent adverse events of any CTCAE grade - summarized by system organ class and CTCAE grade, serious adverse events, deaths summarized by primary cause, and laboratory parameters (hematology and chemistry), vital signs, electrocardiogram data and concomitant medications will be summarized appropriately.
Measure:ORR after crossover following disease progression with single agent gemcitabine hydrochloride
Time Frame:Up to 3 years
Safety Issue:
Description:Subject demographic and baseline characteristics will be summarized by mean, standard deviation, median, minimum, and maximum for continuous variables; and by counts and percentages for categorical variables. Summaries will be provided separately for each treatment group. Treatment group comparisons in ORR will be evaluated using logistic regression and expressed as odds ratios with associated 90% confidence intervals. In the event that rates are low, comparisons will be based on Fisher's exact test.
Measure:ORR, defined as the percentage of subjects achieving a response rating of complete response (CR) or partial response (PR) by RECIST guideline v1.1
Time Frame:Up to 3 years
Safety Issue:
Description:Subject demographic and baseline characteristics will be summarized by mean, standard deviation, median, minimum, and maximum for continuous variables; and by counts and percentages for categorical variables. Summaries will be provided separately for each treatment group. Treatment group comparisons in ORR will be evaluated using logistic regression and expressed as odds ratios with associated 90% confidence intervals. In the event that rates are low, comparisons will be based on Fisher's exact test.
Measure:OS
Time Frame:Number of days from the day the subject received the first dose of protocol therapy until date of death (regardless of cause), assessed up to 3 years
Safety Issue:
Description:OS will be summarized using Kaplan-Meier analyses and compared between the two arms using the logrank test. OS will additionally be analyzed using a Cox proportional hazards model, including the stratification factor, and will be used to estimate the hazard ratio of the gemcitabine hydrochloride/ATR kinase inhibitor VX-970 arm relative to the gemcitabine hydrochloride alone arm and the associated 90% confidence interval.
Measure:PFS
Time Frame:Number of days from the day the subject received the first dose of protocol therapy to the date of documented progressive disease by RECIST version 1.1 or death (regardless of cause), assessed at 6 months
Safety Issue:
Description:PFS will be summarized using Kaplan-Meier analyses and compared between the two arms using the logrank test. PFS will additionally be analyzed using a Cox proportional hazards model, including the stratification factor, and will be used to estimate the hazard ratio of the gemcitabine hydrochloride/ATR kinase inhibitor VX-970 arm relative to the gemcitabine hydrochloride alone arm and the associated 90% confidence interval.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

April 20, 2017