M6620 and Irinotecan Hydrochloride in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
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| ClinicalTrials.gov Identifier: NCT02595931 |
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Recruitment Status :
Recruiting
First Posted : November 4, 2015
Last Update Posted : May 4, 2021
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Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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Brief 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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Metastatic Malignant Solid Neoplasm Refractory Malignant Solid Neoplasm Unresectable Malignant Solid Neoplasm | Drug: Berzosertib Drug: Irinotecan Hydrochloride | Phase 1 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 51 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase I Clinical Trial of M6620 in Combination With the Topoisomerase I Inhibitor Irinotecan in Patients With Advanced Solid Tumors |
| Actual Study Start Date : | June 8, 2016 |
| Estimated Primary Completion Date : | April 30, 2022 |
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| Arm | Intervention/treatment |
|---|---|
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Experimental: Treatment (irinotecan, M6620)
Patients 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.
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Drug: Berzosertib
Given IV
Other Names:
Drug: Irinotecan Hydrochloride Given IV
Other Names:
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Primary Outcome Measures :
- Maximum tolerated dose (MTD) [ Time Frame: Up to 28 days ]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.
- Recommended phase 2 dose (RP2D) of ATR kinase inhibitor M6620 (VX-970) and irinotecan hydrochloride [ Time Frame: Up to 28 days ]The RP2D will be determined based on MTD and the feasibility of the administration.
Secondary Outcome Measures :
- Incidence of adverse events of VX-970 and irinotecan hydrochloride [ Time Frame: Up to 6 months after completion of study treatment ]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.
- Overall response rate [ Time Frame: Up to 6 months after completion of study treatment ]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.
- Incidence of stable disease [ Time Frame: Up to 6 months after completion of study treatment ]Tabulated by disease diagnosis and by dose level. Will also report the response rate and confidence limits at that dose level separately.
- 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 ]Estimated using the Kaplan-Meier method and the corresponding 95% confidence interval will be provided.
- 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) ]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.
- Pharmacodynamic parameters of VX-970 in combination with irinotecan hydrochloride [ Time Frame: Up to day 15 of cycle 1 (each cycle = 28 days) ]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.
Other Outcome Measures:
- Change in biomarker levels [ Time Frame: Baseline to up 6 months after completion of study treatment ]Paired t tests will be used to compare biomarker levels before and after treatment. The Benjamini and Hochberg's procedure will be used to control the false discovery rate at 30%. A descriptive analysis of patient tumor genotype and response to therapy will be performed.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
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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:
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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
- Immunotherapy < 4 weeks prior to entering the study
- 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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02595931
Locations
Show 23 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Liza C Villaruz | University of Pittsburgh Cancer Institute LAO |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT02595931 |
| Other Study ID Numbers: |
NCI-2015-01915 NCI-2015-01915 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) HCC 15-164 UPCI 15-164 9938 ( Other Identifier: University of Pittsburgh Cancer Institute LAO ) 9938 ( Other Identifier: CTEP ) UM1CA186689 ( U.S. NIH Grant/Contract ) UM1CA186690 ( U.S. NIH Grant/Contract ) UM1CA186704 ( U.S. NIH Grant/Contract ) UM1CA186717 ( U.S. NIH Grant/Contract ) |
| First Posted: | November 4, 2015 Key Record Dates |
| Last Update Posted: | May 4, 2021 |
| Last Verified: | April 2021 |
Additional relevant MeSH terms:
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Neoplasms Irinotecan Camptothecin Topoisomerase I Inhibitors Topoisomerase Inhibitors |
Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Antineoplastic Agents, Phytogenic |