What is the mechanism of action of this treatment?

Common treatments for Chronic Lymphocytic Leukemia (CLL) include targeted therapies such as PARP inhibitors and agents targeting DNA damage repair (DDR) pathways. Olaparib, a PARP inhibitor, works by preventing cancer cells from repairing their DNA, leading to cell death, especially in cells with existing DNA repair deficiencies. RP-3500, likely a novel DDR pathway agent, would similarly exploit the impaired DNA repair mechanisms in CLL cells. These treatments are crucial for CLL patients as they offer a more precise approach, targeting the cancer cells' vulnerabilities while sparing normal cells, potentially leading to better outcomes and fewer side effects compared to traditional chemotherapy.

What side effects are associated with this type of intervention?

Common side effects of treatments for Chronic Lymphocytic Leukemia, particularly those involving PARP inhibitors like olaparib and novel agents targeting DDR pathways such as RP-3500, include hematologic toxicities such as anemia, neutropenia, and thrombocytopenia. Non-hematologic side effects often reported are nausea, fatigue, vomiting, and anorexia. These treatments can also lead to more severe complications like myelodysplastic syndrome and acute myeloid leukemia in some cases. Managing these side effects typically involves dose adjustments and supportive care.

What prior FDA approvals exist?

The FDA has approved several treatments for Chronic Lymphocytic Leukemia (CLL) that target DNA damage repair pathways. Venetoclax, a BCL-2 inhibitor, is approved for CLL and works by promoting apoptosis in cancer cells with defective DNA repair mechanisms. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is another approved treatment that indirectly affects DNA repair by inhibiting signaling pathways crucial for CLL cell survival. While olaparib, a PARP inhibitor, is primarily approved for cancers like ovarian and breast cancer, it is being studied for its potential in CLL due to its ability to prevent DNA repair in cancer cells. The combination of RP-3500, a novel DDR pathway-targeting agent, with olaparib is currently under investigation, reflecting ongoing efforts to enhance CLL treatment by exploiting DNA repair vulnerabilities.

What other types of research exist?

Promising novel alternatives for CLL treatment in 2024 may include other DDR pathway inhibitors such as ATR inhibitors (e.g., berzosertib) and other PARP inhibitors like niraparib and rucaparib. Additionally, novel targeted therapies such as BTK inhibitors (e.g., zanubrutinib) and BCL-2 inhibitors (e.g., venetoclax) are also emerging as effective treatments for CLL.

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PARP Inhibitor

RP-3500 + Olaparib for Chronic Lymphocytic Leukemia (CORONADO CLL Trial)

Phase 1 & 2

Waitlist Available

Led By Boyu Hu, MD

Research Sponsored by University of Utah

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Age ≥18 years

Immunophenotype consistent with CLL

Must not have

Prior history of certain malignancies

Recent stem cell transplant or active graft-versus-host disease

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 10 years

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a combination of camonsertib and olaparib in patients with a specific type of blood cancer who have not responded to other treatments. The drugs aim to block the cancer cells' ability to fix their damaged DNA, causing them to die. Olaparib is an oral medication that blocks DNA repair pathways and has shown promising results in various cancers, including breast, ovarian, and prostate cancers.

Who is the study for?

Adults (≥18 years) with chronic lymphocytic leukemia that's relapsed or refractory after at least two treatments. They must have specific genetic mutations, adequate organ function, and no major health issues like severe liver impairment or active central nervous system involvement. Participants need to be able to swallow pills, follow the study schedule, and use effective contraception.

What is being tested?

The trial is testing a combination of two drugs: RP-3500 and Olaparib in patients whose leukemia cells show deficiencies in DNA damage repair pathways. It's an open-label phase Ib/II study which means everyone gets the treatment combo and researchers track its effects.

What are the potential side effects?

While not explicitly listed here, common side effects for cancer drugs like RP-3500 and Olaparib may include nausea, fatigue, low blood cell counts leading to increased infection risk or bleeding problems, diarrhea or constipation. Specific side effects will be monitored throughout the trial.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am 18 years old or older.

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My blood cancer type matches CLL.

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I can swallow pills.

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I have been diagnosed with chronic lymphocytic leukemia.

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My condition did not improve after 2 previous treatments.

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I can take care of myself and perform daily activities.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have had cancer before.

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I recently had a stem cell transplant or I have active graft-versus-host disease.

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I have had lung inflammation or lung disease in the past.

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I have a serious liver condition.

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I am not taking any strong medication that affects liver enzymes or certain drug transporters.

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I have a condition that affects my stomach or intestines.

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My condition has progressed to Richter's Transformation.

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My chronic lymphocytic leukemia (CLL) has spread to my brain.

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I need steroids for my health condition.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 10 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 10 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 10 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Overall response rate (ORR)

Rate of dose-limiting toxicities (DLTs) during the DLT evaluation period

Secondary study objectives

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.

Overall Survival (OS) as defined as the time from registration until death from any cause

Progression-free survival (PFS) as defined as the time from study drug initiation to the time documented disease progression (as assessed by 2018 iwCLL criteria) or death from any cause

+1 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

6Treatment groups

Experimental Treatment

Group I: Phase Ib: Dose Level 3Experimental Treatment2 Interventions

To assess the MTD of RP-3500 in combination with olaparib. Patients will receive 80mg of RP-3500 daily and 150mg Olaparib BID.

Group II: Phase Ib: Dose Level 2Experimental Treatment2 Interventions

To assess the MTD of RP-3500 in combination with olaparib. Patients will receive 80mg of RP-3500 daily and 100mg Olaparib BID.

Group III: Phase Ib: Dose Level 1Experimental Treatment2 Interventions

To assess the MTD of RP-3500 in combination with olaparib. Patients will receive 50mg of RP-3500 daily and 100mg Olaparib BID.

Group IV: Phase Ib: Dose Level -1Experimental Treatment2 Interventions

To assess the MTD of RP-3500 in combination with olaparib. Patients will receive 40mg of RP-3500 daily and 100mg Olaparib BID.

Group V: Phase II: Dose Expansion Enrichment CohortExperimental Treatment2 Interventions

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

Group VI: Phase II: Dose Expansion Eligible Subjects CohortExperimental Treatment1 Intervention

Cohort will include all other eligible subjects for Dose Expansion.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Olaparib

2007

Completed Phase 4

~2190

0 / 15Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Chronic Lymphocytic Leukemia (CLL) include targeted therapies such as PARP inhibitors and agents targeting DNA damage repair (DDR) pathways. Olaparib, a PARP inhibitor, works by preventing cancer cells from repairing their DNA, leading to cell death, especially in cells with existing DNA repair deficiencies. RP-3500, likely a novel DDR pathway agent, would similarly exploit the impaired DNA repair mechanisms in CLL cells. These treatments are crucial for CLL patients as they offer a more precise approach, targeting the cancer cells' vulnerabilities while sparing normal cells, potentially leading to better outcomes and fewer side effects compared to traditional chemotherapy.

Poly(ADP-ribose) polymerase inhibitor CEP-8983 synergizes with bendamustine in chronic lymphocytic leukemia cells in vitro.PARP1 expression, activity and ex vivo sensitivity to the PARP inhibitor, talazoparib (BMN 673), in chronic lymphocytic leukaemia.