Combination Therapy in Cancers With Mutations in DNA Repair Genes
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age18+
SponsorUniversity of California, San Francisco
About this trial
The purpose of this phase 1 clinical trials is to determine whether niraparib (a Poly (ADP-ribose) polymerase inhibitor (PARPi)) can be safely combined with irinotecan with manageable toxicity and reasonable efficacy. Emerging evidence suggest that PARPi is an effective therapeutic strategy in a wider subset of solid tumors that may have defective homologous recombination (HR) or DNA repair gene mutations. BReast CAncer gene (BRCA), partner and localizer of BRCA2 (PALB2), and various other DNA repair germline mutations predispose carriers to cancers of the breast, ovaries, pancreas, prostate and melanoma. A number of preclinical studies have demonstrated that PARP inhibitors can work as chemopotentiators. There is significant interest in this combination, and the recommended phase II dose will be used in the upcoming NCI ComboMatch trial.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Individuals 18 years of age or older.
Ability to understand and willingness to voluntarily sign a written informed consent document prior to any study-related assessments or procedures are conducted; and willing and able to adhere to the study visit schedule and other protocol requirements.
Presence of at least one lesion with measurable disease as defined by RECIST 1.1 criteria for response assessment
Advanced solid tumor malignancy without curative options
Disqualifiers
Any significant medical condition, laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study at clinician's discretion and not otherwise stated below.
Prior allergic reaction to PARP inhibitor or irinotecan or their excipients. Prior PARP inhibitor or irinotecan (or topoisomerase 1 inhibitors) use is allowed.
Individuals with known toxicity to irinotecan (e.g., grade 3 or 4 neutropenia) or suspected sensitivity.
Individuals with homozygous or compound heterozygous UGT1A1 polymorphisms (e.g., alleles *28/*28, *6/*6, or *6/*28) predicted to be associated with medium-to-high risk of irinotecan-related toxicity
Trial design
Design model
Sequential
Treatments tested in this trial
Niraparib
DrugGiven orally
Irinotecan
DrugGiven intravenously (IV)
Treatment groups
24 Participants
are divided into 6 treatment groups6
Treatment groupsSee each treatment group below.
Group A: Cohort 1 (Niraparib, Irinotecan)Experimental treatment 2 interventions
Group B: Cohort 2 (Niraparib, Irinotecan)Experimental treatment 2 interventions
Group C: Cohort 3a (Niraparib, Irinotecan)Experimental treatment 2 interventions
Group D: Cohort 3b (Niraparib, Irinotecan)Experimental treatment 2 interventions
Group E: Cohort 4a (Niraparib, Irinotecan)Experimental treatment 2 interventions
Group F: Cohort 4b (Niraparib, Irinotecan)Experimental treatment 2 interventions
Trial outcomes
Primary outcomes
1
Percentage of participants with treatment-emergent adverse events
The percentage of participants with treatment-emergent adverse events as classified and graded by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5 will be reported
Time frame
30 days after the last dose2
Maximum Tolerated Dose (MTD)
The MTD is defined as the highest dose studied for which the observed incidence of DLT is less than 33% or occurs within at most one out of six patients treated at any given dose level.
Time frame
30 days after the last dose3
Percentage of participants with Dose Limiting Toxicities (DLTs)
The percentage of participants with documented dose-limiting toxicities will be reported by dose level.
Time frame
30 days after the last dose4
Recommended Phase 2 Dose (RP2D)
The RP2D will be selected based on the evaluation of dose-limiting toxicities and adverse events measured using CTCAE v5.0.
Time frame
Up to 2 yearsSecondary outcomes
1
Overall response rate (ORR)
Defined as the proportion of participants who achieve a Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 best overall response of confirmed complete response (CR) or confirmed partial response (PR)
Time frame
Up to 2 years2
Duration of overall response (DOR)
Defined as the duration of time from when measurement criteria are met for CR or PR (whichever is first recorded) until the date that recurrent/ progressive disease (PD) is objectively documented (taking as reference for PD the smallest measurements recorded since the treatment started).
Time frame
Up to 2 years3
Median duration of stable disease (SD)
Defined as the duration of time from measurement criteria are met for SD or better until the date that recurrent/ progressive disease (PD) is objectively documented (taking as reference for PD the smallest measurements recorded since the treatment started).
Time frame
Up to 2 years4
Median Progression-Free Survival (PFS)
Defined as the duration of time from start of treatment to time of disease recurrence/ progression (PD) or death from any cause, whichever occurs first.
Time frame
Up to 2 yearsSponsors and contacts
Click on the lead sponsor to view all of their trials.
University of California, San Francisco
Lead sponsor
GlaxoSmithKline
Collaborator
Source ClinicalTrials.gov