Summary

Eligibility
for people ages 18 years and up (full criteria)
Location
at UC Davis UCSF
Dates
study started
Principal Investigator
by Karen L. Kelly (ucdavis)

Description

Summary

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.

Official Title

Phase I Clinical Trial of M6620 in Combination With the Topoisomerase I Inhibitor Irinotecan in Patients With Advanced Solid Tumors

Details

PRIMARY OBJECTIVE:

  1. 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:

  1. 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:

  1. 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.

Keywords

Metastatic Malignant Neoplasm Refractory Malignant Neoplasm Unresectable Malignant Neoplasm Neoplasms Irinotecan Camptothecin Berzosertib Irinotecan Hydrochloride

Eligibility

You can join if…

Open to people ages 18 years and up

  • 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 m2

  • 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

You CAN'T join if...

  • 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

Locations

  • University of California Davis Comprehensive Cancer Center accepting new patients
    Sacramento California 95817 United States
  • UCSF Medical Center-Mount Zion in progress, not accepting new patients
    San Francisco California 94115 United States

Lead Scientist at UC Cancer

  • Karen L. Kelly (ucdavis)
    Professor, Hematology and Oncology. Authored (or co-authored) 165 research publications.

Details

Status
accepting new patients
Start Date
Sponsor
National Cancer Institute (NCI)
ID
NCT02595931
Phase
Phase 1
Study Type
Interventional
Last Updated