Clinical Trials /

M6620 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 M6620 and irinotecan hydrochloride in treating patients with solid tumors that have spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). M6620 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: M6620 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 M6620 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: HCC 15-164
  • SECONDARY ID: UPCI 15-164
  • SECONDARY ID: 9938
  • SECONDARY ID: 9938
  • SECONDARY ID: UM1CA186689
  • SECONDARY ID: UM1CA186690
  • SECONDARY ID: UM1CA186704
  • SECONDARY ID: UM1CA186717
  • NCT ID: NCT02595931

Conditions

  • Metastatic Malignant Neoplasm
  • Refractory Malignant Neoplasm
  • Unresectable Malignant Neoplasm

Interventions

DrugSynonymsArms
Berzosertib2-Pyrazinamine, 3-(3-(4-((Methylamino)methyl)phenyl)-5-isoxazolyl)-5-(4-((1-methylethyl)sulfonyl)phenyl)-, M 6620, M6620, VX 970, VX-970, VX970Treatment (irinotecan, M6620)
Irinotecan HydrochlorideCampto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, Irinomedac, Irinotecan Hydrochloride Trihydrate, Irinotecan Monohydrochloride Trihydrate, U-101440ETreatment (irinotecan, M6620)

Purpose

This phase I trial studies the side effects and best dose of M6620 and irinotecan hydrochloride in treating patients with solid tumors that have spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). M6620 and irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of
      berzosertib (M6620) in combination with irinotecan hydrochloride (irinotecan) in patients
      with advanced solid tumors.

      SECONDARY OBJECTIVES:

      I. To estimate the safety and tolerability of M6620 in combination with irinotecan.

      II. To document anti-tumor activity. III. To determine the pharmacokinetic (PK) and
      pharmacodynamic (PD) parameters of M6620 and irinotecan.

      EXPLORATORY OBJECTIVE:

      I. To identify molecular subpopulations of patients with increased sensitivity to the
      irinotecan and M6620 combination.

      OUTLINE: This is a dose-escalation study.

      Patients receive irinotecan hydrochloride intravenously (IV) over 90 minutes and M6620 IV
      over 60 minutes on days 1 and 15. Treatment repeats every 28 days for 12 cycles 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, M6620)ExperimentalPatients receive irinotecan hydrochloride IV over 90 minutes and M6620 IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
  • Berzosertib
  • 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 M6620]);
             patients enrolled to this cohort should have tumors deemed easily accessible for
             biopsies with low likelihood of complication

          -  The effects of M6620 on the developing human fetus are unknown; for this reason and
             because deoxyribonucleic acid (DNA)-damage response (DDR) inhibitors may have
             teratogenic potential, 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
             administration

               -  For this reason and because DNA-damage response (DDR) inhibitors may have
                  teratogenic potential, 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 other systemic therapy or radiotherapy or
             patients who have not recovered from adverse events due to prior administered agents
             as follows:

               -  Chemotherapy < 4 weeks prior to entering the study

               -  Radiotherapy < 4 weeks prior to entering the study

               -  Nitrosoureas/mitomycin C < 6 weeks prior to entering the study

               -  Targeted therapy < 2 weeks (or 5 half-lives, whichever is longer) prior to
                  entering the study

               -  Those who have not recovered from clinically significant adverse events due to
                  prior agents administered to grade =< 1 or baseline, with exception of alopecia
                  and peripheral neuropathy, unless approved by the protocol chair

          -  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 M6620 or irinotecan

          -  M6620 is primarily metabolized by CYP3A4; irinotecan and its active metabolite, SN-38,
             are metabolized by CYP3A4 and UGT1A1, respectively; therefore, concomitant
             administration with strong inhibitors or inducers of CYP3A4 should be avoided;
             valproic acid is known to inhibit the process of glucuronidation and may potentially
             enhance the toxicity of irinotecan; 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 because M6620 as a DNA-damage response
             (DDR) inhibitor may have the potential for teratogenic or abortifacient effects;
             because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with M6620, breastfeeding should be discontinued
             if the mother is treated with M6620; these potential risks may also apply to other
             agents used in this study

          -  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 because of the potential for pharmacokinetic interactions with
             M6620; patients with poorly controlled HIV are not eligible due to the increased risk
             of lethal infections when treated with marrow-suppressive therapy
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:Incidence of adverse events of VX-970 and irinotecan hydrochloride
Time Frame:Up to 6 months after completion of study treatment
Safety Issue:
Description:Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. 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:Overall response rate
Time Frame:Up to 6 months after completion of study treatment
Safety Issue:
Description:Will be evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1. 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:Incidence of stable disease
Time Frame:Up to 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:Progression-free survival
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:Pharmacokinetic parameters of VX-970 in combination with irinotecan hydrochloride
Time Frame:Days -14 through -11, 1, and 15 through 18 of cycle 1 (each cycle = 28 days)
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 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.
Measure:Pharmacodynamic parameters of VX-970 in combination with irinotecan hydrochloride
Time Frame:Up to day 15 of cycle 1 (each cycle = 28 days)
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 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.

Details

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

Last Updated

December 16, 2020