Clinical Trials /

VX-970 and Irinotecan Hydrochloride in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

NCT02595931

Description:

This phase I trial studies the side effects and best dose of ATR kinase inhibitor M6620 (VX-970) and irinotecan hydrochloride in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced) or cannot be removed by surgery. VX-970 and irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: ATR Kinase Inhibitor VX-970 and Irinotecan Hydrochloride in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
  • Official Title: Phase I Clinical Trial of VX-970 in Combination With the Topoisomerase I Inhibitor Irinotecan in Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-01915
  • SECONDARY ID: NCI-2015-01915
  • SECONDARY ID: UPCI 15-164
  • SECONDARY ID: 9938
  • SECONDARY ID: 9938
  • SECONDARY ID: P30CA047904
  • SECONDARY ID: UM1CA186689
  • SECONDARY ID: UM1CA186690
  • SECONDARY ID: UM1CA186704
  • SECONDARY ID: UM1CA186717
  • NCT ID: NCT02595931

Conditions

  • Advanced Malignant Solid Neoplasm
  • Metastatic Malignant Neoplasm
  • Metastatic Malignant Solid Neoplasm
  • Refractory Malignant Neoplasm
  • Unresectable Malignant Neoplasm
  • Unresectable Solid Neoplasm

Interventions

DrugSynonymsArms
ATR Kinase Inhibitor VX-970VX-970Treatment (irinotecan hydrochloride, VX-970)
Irinotecan HydrochlorideCampto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, Irinomedac, U-101440ETreatment (irinotecan hydrochloride, VX-970)

Purpose

This phase I trial studies the side effects and best dose of ATR kinase inhibitor VX-970 and irinotecan hydrochloride in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced) or cannot be removed by surgery. ATR kinase inhibitor VX-970 and irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ATR
      kinase inhibitor VX-970 (VX-970) in combination with irinotecan hydrochloride (irinotecan)
      in patients with advanced solid tumors.

      SECONDARY OBJECTIVES:

      I. To estimate the safety and tolerability of VX-970 in combination with irinotecan.

      II. To document anti-tumor activity. Anti-tumor activity will be measured by overall
      response rate (ORR) and progression-free survival (PFS).

      III. To determine the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of VX-970 and
      irinotecan.

      TERTIARY OBJECTIVES:

      I. To identify molecular subpopulations of patients with increased sensitivity to the
      irinotecan and VX-970 combination.

      OUTLINE: This is a dose-escalation study.

      Patients receive irinotecan hydrochloride intravenously (IV) over 90 minutes and ATR kinase
      inhibitor VX-970 IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for 12
      courses in the absence of disease progression or unacceptable toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Treatment (irinotecan hydrochloride, VX-970)ExperimentalPatients receive irinotecan hydrochloride IV over 90 minutes and ATR kinase inhibitor VX-970 IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.
  • ATR Kinase Inhibitor VX-970
  • Irinotecan Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed metastatic or unresectable malignancy
             that is refractory to standard therapy or for which no standard therapy exists and
             where irinotecan is deemed a reasonable treatment option

          -  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

          -  No limit on prior lines of therapy for metastatic disease; prior adjuvant or
             neoadjuvant chemotherapy does not count as a prior line of therapy as long as
             completion of the adjuvant or neoadjuvant therapy was more than 1 year prior to
             patient enrollment

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

          -  Life expectancy of greater than 12 weeks

          -  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 x institutional upper limit of normal (ULN); if liver involvement, =< 5 x ULN

          -  Creatinine clearance >= 60 mL/min/1.73 m^2

          -  Patients must have archived tumor tissue from prior tumor biopsy or surgical
             resections available for submission that is sufficient to complete molecular
             profiling

          -  FOR PATIENTS ENROLLED IN THE EXPANSION COHORT: willingness to undergo mandatory
             biopsies (day -14, approximately 4 hours post end of irinotecan infusion and day 1,
             approximately 4 hours post end of irinotecan infusion [= 3 hours post end of
             VX-970]); patients enrolled to this cohort should have tumors deemed easily
             accessible for biopsies with low likelihood of complication

          -  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 VX-970 administration; 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, for the duration
             of study participation and for 6 months after study completion

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

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from clinically significant adverse events due to prior agents administered
             to =< grade 1 or baseline with the exception of alopecia and peripheral neuropathy,
             unless approved by the protocol chair

          -  Patients with uridine diphosphate (UDP) glucuronosyltransferase 1 family, polypeptide
             A cluster (UGT1A)1*1/*28 genotype or *28/*28 genotype

          -  Patients who are receiving any other investigational agents

          -  Patients with unstable brain metastases should be excluded; however, patients with
             known brain metastases may participate in this clinical trial if they are clinically
             stable (without evidence of progression by imaging for at least four weeks prior to
             the first dose of trial treatment and any neurologic symptoms have returned to
             baseline), have no evidence of new or enlarging brain metastases, and are on a stable
             or decreasing dose of steroids for at least 14 days prior to trial treatment

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to VX-970 or irinotecan

          -  Concomitant administration with strong inhibitors or inducers of CYP3A4 should be
             avoided; ; medications that enhance glucuronidation (i.e. phenytoin, phenobarbital,
             carbamazepine, rifampin, etc.) may also enhance clearance of SN-38, which may
             possibly decrease efficacy; therefore, concomitant administration of these drugs
             should be avoided; because the lists of these agents are constantly changing, it is
             important to regularly consult a frequently-updated medical reference for a list of
             drugs to avoid or minimize use of; 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, severe active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements; patients with chronic viral hepatitis may participate in this
             clinical trial if they are clinically stable with acceptable liver function

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with VX-970

          -  Human immunodeficiency virus (HIV)-positive patients with well-controlled disease, as
             determined by CD4 count and viral load, who are on antiretroviral therapy that does
             not contain a strong inducer or inhibitor of CYP3A4 (e.g. regimens containing
             ritonavir, cobicistat, efavirenz or etravirine) are allowed on trial; HIV-positive
             patients on combination antiretroviral therapy with strong inducers or inhibitors of
             CYP3A4 are ineligible; patients with poorly controlled HIV are not eligible
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:MTD, defined as the highest dose level at which =< 20% patients experience dose limiting toxicity
Time Frame:28 days
Safety Issue:
Description:A logistic regression model will be used to determine the MTD using all patients.

Secondary Outcome Measures

Measure:Incidence of adverse events of ATR kinase inhibitor and irinotecan hydrochloride, using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up 6 months after completion of study treatment
Safety Issue:
Description:A toxicity will be considered to be an adverse event that is possibly, probably or definitely related to treatment. The maximum grade of toxicity for each category of interest will be recorded for each patient, and the summary results will be tabulated by category, grade, and dose level. Serious (>= grade 3) toxicities will be described on a patient-by-patient basis and will include any relevant baseline data.
Measure:Incidence of stable disease
Time Frame:Up 6 months after completion of study treatment
Safety Issue:
Description:Tabulated by disease diagnosis and by dose level. Will also report the response rate and confidence limits at that dose level separately.
Measure:ORR, evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1
Time Frame:Up 6 months after completion of study treatment
Safety Issue:
Description:Tabulated by disease diagnosis and by dose level. Will also report the 95% confidence limits on the response rates. Will also report the response rate and confidence limits at that dose level separately.
Measure:PD parameters of ATR kinase inhibitor VX-970 in combination with irinotecan hydrochloride
Time Frame:Up day 15 of course 1
Safety Issue:
Description:Within-subject comparison of day 15 and day -14 irinotecan hydrochloride and SN38 AUC and t1/2 will be performed. Cmax, AUC, t1/2, CL, and Vss of ATR kinase inhibitor VX-970 with single-agent historical data at comparable doses will be compared. Induction of gamma H2AX as a marker of ATR-dependent replication stress in PBMCs and tumor will be characterized.
Measure:PFS
Time Frame:Duration of time from start of treatment to time of progression or death, whichever occurs first, assessed up 6 months after completion of study treatment
Safety Issue:
Description:Estimated using the Kaplan-Meier method and the corresponding 95% confidence interval will be provided.
Measure:PK parameters of ATR kinase inhibitor VX-970 in combination with irinotecan hydrochloride
Time Frame:Days -14 through -11, 1, and 15 through 18 of course 1
Safety Issue:
Description:Within-subject comparison of day 15 and day -14 irinotecan hydrochloride and SN38 area under the curve (AUC) and half-life (t1/2) will be performed. Maximum concentration (Cmax), AUC, t1/2, clearance (CL), and volume in steady state (Vss) of ATR kinase inhibitor VX-970 with single-agent historical data at comparable doses will be compared. Induction of gamma H2AX as a marker of ATR-dependent replication stress in peripheral blood mononuclear cells (PBMCs) and tumor will be characterized.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

April 12, 2017