RP-3500 and Olaparib in DNA Damage Repair Pathway Deficient Relapsed/Refractory Chronic Lymphocytic Leukemia

NCT05405309 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: HCI141431
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label, multicenter, phase Ib/II study of the combination of RP-3500 and olaparib in Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) patients with DDR deficiencies.

Conditions

Chronic Lymphocytic Leukemia

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) of Camonsertib (RP-3500) in Combination With Olaparib

  This outcome will report the number of patients who experienced a Dose-Limiting Toxicity (DLT) in Phase Ib Dose Level 1, Phase Ib Dose Level 2, Phase Ib Dose Level 3, and Phase Ib Dose Level -1 during the DLT window (Cycle 1 Day 1 to Cycle 1 Day 21). A keyboard phase I design was employed; the target toxicity was 30% with an equivalence interval between 25-33% of patients. The first 5 patients were treated at DL-1 (camonsertib 40mg daily and olaparib 100mg BID dosing 3 days per week).

  up to 28 days after initiation of study drug

• Overall Response

  This outcome will assess the overall responseof combination RP-3500 and olaparib. Overall response is defined by the count of subjects achieving any confirmed partial (PR) and complete response (CR) as assessed by 2018 International Working Group on Chronic Lymphocytic Leukemia (iwCLL) response criteria. Subjects without a baseline/screening tumor assessment or at least one on-treatment assessment will be considered non-responders.

  up to 85 Days after initiation of study drug

Secondary Outcomes (4)

• Adverse Events (AE) by Grade

  up to 28 days after the last dose of study treatment (up to 113 days after initiation of study drug)

• Progression-free Survival (PFS)

  up to 15 months from initiation of study treatment

• Overall Survival (OS)

  up to 21 months after study registration

• Duration of Response (DoR) as Defined as the Interval of Time From the Date of Initial Documented Response (PR or Better as Per 2018 iwCLL Criteria for Response) to the Time of Progression.

  up to 21 months after initiation of study treatment.

Study Arms (7)

Phase Ib: Dose Level -1

EXPERIMENTAL

To assess the MTD of RP-3500 in combination with olaparib. Patients will receive RP-3500 40mg daily and olaparib 100mg BID. Both drugs are given with intermittent dosing of 2 days per week and each cycle is 21 days.

Drug: RP-3500; Drug: Olaparib

Phase Ib: Dose Level 1

EXPERIMENTAL

To assess the MTD of RP-3500 in combination with olaparib. Patients will receive RP-3500 50mg daily and olaparib 100mg BID. Both drugs are given with intermittent dosing of 2 days per week and each cycle is 21 days.

Drug: RP-3500; Drug: Olaparib

Phase Ib: Dose Level 2

EXPERIMENTAL

To assess the MTD of RP-3500 in combination with olaparib. Patients will receive RP-3500 80mg daily and olaparib 100mg BID. Both drugs are given with intermittent dosing of 2 days per week and each cycle is 21 days.

Drug: RP-3500; Drug: Olaparib

Phase Ib: Dose Level 3

EXPERIMENTAL

To assess the MTD of RP-3500 in combination with olaparib. Patients will receive RP-3500 80mg daily and olaparib 150mg BID. Both drugs are given with intermittent dosing of 2 days per week and each cycle is 21 days.

Drug: RP-3500; Drug: Olaparib

Phase II: Dose Expansion Enrichment Cohort

EXPERIMENTAL

Subjects enrolled into the enrichment cohort must have a del(11q) and/or ATM mutation.

Drug: RP-3500; Drug: Olaparib

Phase II: Dose Expansion Eligible Subjects Cohort

EXPERIMENTAL

Cohort will include all other eligible subjects for Dose Expansion.

Drug: RP-3500

Phase Ib (prior to Aug2023 amendment): Original Dose Level 1

EXPERIMENTAL

To assess the MTD of RP-3500 in combination with olaparib. Before the Aug2023 amendment, patients enrolled at Dose Level 1 received RP-3500 40mg daily and olaparib 100mg BID. Both drugs were given with intermittent dosing of 3 days per week and each cycle was 28 days.

Drug: RP-3500; Drug: Olaparib

Interventions

RP-3500 DRUG

RP-3500 is a highly potent and selective Ataxia telangiectasia and Rad3 related inhibitor (ATRi) and has demonstrated significant preclinical activity.

Phase II: Dose Expansion Eligible Subjects Cohort; Phase II: Dose Expansion Enrichment Cohort; Phase Ib (prior to Aug2023 amendment): Original Dose Level 1; Phase Ib: Dose Level -1; Phase Ib: Dose Level 1; Phase Ib: Dose Level 2; Phase Ib: Dose Level 3

Olaparib DRUG

Olaparib is an oral poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) that inhibits PARP's function by competitively binding to the Nicotinamide adenine dinucleotide (NAD+) binding site, which PARP requires as a cofactor to operate.

Phase II: Dose Expansion Enrichment Cohort; Phase Ib (prior to Aug2023 amendment): Original Dose Level 1; Phase Ib: Dose Level -1; Phase Ib: Dose Level 1; Phase Ib: Dose Level 2; Phase Ib: Dose Level 3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of Chronic lymphocytic leukemia (CLL) according to the National Cancer Institute International Workshop on Chronic Lymphocytic Leukemia (NCI/IWCLL), criteria.
• This includes previous documentation of:
• Biopsy-proven small lymphocytic lymphoma/CLL
• Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the following:
• Peripheral blood monoclonal B cell population of greater than 5x109/L
• Immunophenotype consistent with CLL defined as:
• The predominant population of lymphocytes share both B cell antigens \[CD19, CD20 (typically dim expression), or CD23\] as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc).
• Clonality as evidenced by κ or λ light chain restriction (typically dim immunoglobulin expression)
• Negative Fluorescence in situ hybridization (FISH) analysis for t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy (e.g. marrow aspirate), or negative immunohistochemical stains for cyclin D1 on involved tissue biopsy (e.g. marrow aspirate or lymph node biopsy).
• Repeat testing of somatic mutations and FISH analysis must be performed by a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory after progression is noted from most recent line of therapy and within 6 months of screening. Primary CLL cells must harbor one of these abnormalities:
• Somatic gene mutation testing shows mutation(s) in Tumor protein P53 (TP53), Ataxia-telangiectasia mutated (ATM), Splicing factor 3b subunit 1 (SF3B1), eukaryotic nuclear export protein exportin-1 (XPO1) and/or Protection of Telomeres Protein 1 (POT1)
• Cytogenetic FISH analysis shows deletion 17p13 and/or deletion 11q22.3
• Relapsed or refractory after at least 2 prior lines of therapy, and in the opinion of the treating Investigator are either not eligible for other approved therapies or no approved therapies are expected to have sustained therapeutic benefit.
• Patient in need of treatment or change in treatment per iwCLL criteria.

You may not qualify if:

• Age ≥18 years
• Eastern Cooperative Oncology Group (ECOG) performance status between 0-2
• Expected life expectancy of at least 12 months per the investigator.
• The following laboratory or clinical values obtained ≤ 42 days prior to enrollment:
• Absolute neutrophil count ≥1000/µL (G-CSF support is allowed) unless documented bone marrow involvement of CLL
• Platelets of ≥50K/µL unless documented bone marrow involvement of CLL
• Creatinine Clearance (CrCl) ≥45 mL/minute as measured by a 24 hour urine collection or calculated by the Cockcroft-Gault Formula
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) unless due to Gilbert's disease. For those patients with previous history of Gilbert's disease, a direct bilirubin should be performed and must be \<1.5mg/dL.
• SGOT (AST)/SGPT (ALT) ≤3.0 x the institutional ULN
• Time from the start of the Q wave to the end of the T wave (QT) corrected for heart rate by Fridericia's cube root formula (QTcF) ≤470 msec
• For patients with prolonged AT interval due to bundle branch block, a "corrected value" ≤470 msec and confirmation by cardiologist that patient is asymptomatic and that no other cardiac conduction or cardiac abnormality is present would pose any safety issues for the patient.
• Recommended correction of QT for patients with bundle branch block are as follows: Patient's Q wave R wave and S wave complex (QRS) is 160 msec, and the measured QT is 510 msec. As the normal QRS is \~120 msec, subtract 120 msec from the measured QRS of the patient (160-120 = 40 msec) and then subtract this result from the measured QT (510-40=470 msec).
• Pulse oximetry reading of ≥90% on room air
• Able to adhere to study visit schedule and other protocol requirements
• Patients must be able to swallow capsules

Sponsors & Collaborators

• University of Utah: lead
• Repare Therapeutics: collaborator

Study Sites (1)

Huntsman Cancer Institute at the University of Utah

Salt Lake City, Utah, 84112, United States

Location

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

olaparib

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: IIT Data Management Team
• Organization: Research Compliance Office, Huntsman Cancer Institute

IITDataManagement@hci.utah.edu

801-213-6215

Study Officials

• Boyu Hu, MD

  Huntsman Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 31, 2022
• First Posted: June 6, 2022
• Study Start: September 23, 2022
• Primary Completion: October 24, 2023
• Study Completion: January 10, 2025
• Last Updated: June 3, 2025
• Results First Posted: June 3, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)