PARG Inhibitor for Advanced Cancers

Recruiting in Palo Alto (17 mi)

+28 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: IDEAYA Biosciences

Must not be taking: Cytotoxic chemotherapy, Radioimmunotherapy

Disqualifiers: CNS malignancy, Cardiac abnormalities, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called IDE161 to see if it is safe and effective for patients with advanced cancers that have specific genetic changes. The drug works by preventing cancer cells from repairing their DNA, which can lead to their death.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain cancer treatments before enrolling. Specifically, you must not have had chemotherapy, radioimmunotherapy, or treatment with therapeutic antibodies within a specified time before joining the trial.

What data supports the effectiveness of the drug IDE-161, a PARG inhibitor, for advanced cancers?

Research shows that inhibiting PARG can reduce the spread of colon cancer cells, suggesting potential benefits for other cancers. Additionally, similar drugs called PARP inhibitors have been effective in treating various cancers by targeting DNA repair mechanisms, which might indicate a promising role for PARG inhibitors like IDE-161. ^{1 2 3 4 5}

What makes the drug IDE-161 unique for treating advanced cancers?

IDE-161 is a PARG inhibitor, which is different from other treatments like PARP inhibitors, as it targets a different enzyme involved in DNA repair, potentially offering a new approach for treating advanced cancers. ^{1 5 6 7 8}

Research Team

Darrin Beaupre, MD,PhD

Principal Investigator

IDEAYA Biosciences

Eligibility Criteria

This trial is for adults over 18 with advanced solid tumors like ovarian, pancreatic, breast, or prostate cancer. Participants must have genetic changes linked to poor DNA repair and have tried at least one standard treatment without success or couldn't tolerate it. People with brain cancer, recent major surgery, ongoing infections, heart issues, or those who've had certain treatments recently can't join.

Inclusion Criteria

My cancer has worsened after at least one standard treatment or I couldn't tolerate the treatment.

I am 18 years old or older.

My cancer is advanced or has spread but is not a brain tumor.

Exclusion Criteria

I have a diagnosed brain cancer.

I have not had major surgery in the last 4 weeks.

I haven't had chemotherapy in the last 4 weeks.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Monotherapy Dose Escalation

Participants receive IDE161 as a single agent to determine the maximum tolerated dose and recommended dose for expansion

Approximately 2 years

Combination Dose Escalation

Participants receive IDE161 in combination with pembrolizumab to determine the maximum tolerated dose and recommended dose for expansion

Approximately 2 years

Monotherapy Dose Expansion

Further assessment of safety and tolerability of IDE161 monotherapy at the recommended dose for expansion

Approximately 4 years

Combination Dose Expansion

Further assessment of safety and tolerability of IDE161 in combination with pembrolizumab at the recommended dose for expansion

Approximately 4 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• IDE-161 (PARP Inhibitor)

Trial Overview The study tests the safety and effectiveness of a new drug called IDE161 on patients with specific types of advanced cancers. It aims to see how well participants tolerate this drug and its impact on their cancer.

Participant Groups

Group I: Module 2 Part 2: Combination Dose Expansion with pembrolizumab Experimental Treatment 2 Interventions

After a dose is decided in Part 1, participants entering part 2 will be assigned to a dose level.

Group II: Module 2 Part 1: Combination Dose Escalation with pembrolizumab Experimental Treatment 2 Interventions

Participants will be assigned to a dose level.

Group III: Module 1 Part 2: Monotherapy Dose Expansion Experimental Treatment 1 Intervention

After a dose is decided in Part 1, participants entering part 2 will be assigned to a dose level.

Group IV: Module 1 Part 1: Monotherapy Dose Escalation Experimental Treatment 1 Intervention

Participants will be assigned to a dose level.

Who Is Running the Clinical Trial?

IDEAYA Biosciences

Lead Sponsor

Trials

6

Recruited

1,300+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

PARP inhibitors (PARPi) show promise in treating gastrointestinal (GI) cancers, particularly in patients with deficiencies in homologous recombination (HR) DNA repair, similar to their use in other cancer types like breast and ovarian cancers.

Analysis of genomic data from 1744 GI cancer patients suggests that HR status could serve as a predictive biomarker for the efficacy of PARPi, highlighting the potential for personalized treatment strategies in GI malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers. Alhusaini, A., Cannon, A., Maher, SG., et al.[2021]

In a Phase II trial involving 27 patients with germline BRCA1/2-mutant high-grade serous ovarian cancer, 63% were able to safely receive a second course of the PARP inhibitor olaparib, indicating its feasibility for retreatment.

While a second course of olaparib was safe, its efficacy was modest, with only 4 patients (15%) maintaining treatment for 6 months or longer, and common side effects included anemia, nausea, and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-Maintenance Olaparib Therapy in Relapsed, Germline BRCA1/2-Mutant High-Grade Serous Ovarian Cancer (MOLTO): A Phase II Trial. Morgan, RD., Clamp, AR., White, DJ., et al.[2023]

Maintenance therapy with PARP inhibitors (olaparib, niraparib, rucaparib) significantly improves progression-free survival in advanced ovarian cancer patients, with gains of 6 to 8 months compared to placebo.

The analysis included data from 5 randomized studies, confirming the effectiveness of these therapies following platinum-based chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of maintenance treatment with PARP inhibitors in ovarian carcinoma patients responding to platinum therapy: Use of restricted mean survival time as an index of efficacy. Cancanelli, L., Mengato, D., Di Spazio, L., et al.[2022]

Fluzoparib is a novel and potent PARP inhibitor that effectively induces DNA damage and apoptosis in cancer cells lacking homologous recombination repair, showing promise for treating BRCA-mutated cancers.

In preclinical models, fluzoparib demonstrated favorable pharmacokinetics and a better toxicity profile compared to olaparib, while also enhancing the effectiveness of other cytotoxic drugs without increasing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacologic characterization of fluzoparib, a novel poly(ADP-ribose) polymerase inhibitor undergoing clinical trials. Wang, L., Yang, C., Xie, C., et al.[2021]

PARP inhibitors, such as olaparib and talozaparib, are effective treatments for advanced breast cancer in patients with germline BRCA 1 or BRCA 2 variants, showing improved progression-free survival compared to standard treatments in phase III trials.

These medications work by inducing synthetic lethality in cancer cells with impaired DNA damage repair, specifically targeting the vulnerabilities created by these genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perspectives on PARP inhibitors as pharmacotherapeutic strategies for breast cancer. Oh, SY., Rahman, S., Sparano, JA.[2022]

PARP inhibitors (PARPi) have shown effectiveness in treating metastatic breast cancer, not only in patients with BRCA1/2 mutations but also in certain breast cancer cell lines without these mutations, indicating a broader therapeutic potential.

In particular, 5 out of 8 triple-negative breast cancer (TNBC) cell lines were responsive to PARPi, with Talazoparib demonstrating high sensitivity in ER-/HER2+ cells, suggesting that PARPi could be a valuable treatment option for various breast cancer subtypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response of Breast Cancer Cells to PARP Inhibitors Is Independent of BRCA Status. Keung, MY., Wu, Y., Badar, F., et al.[2022]

The combination of pamiparib (a PARP inhibitor) and tislelizumab (an anti-PD-1 antibody) was generally well tolerated in a study of 49 patients with advanced solid tumors, with a recommended phase 2 dose established as tislelizumab 200 mg every 3 weeks plus pamiparib 40 mg twice daily.

Out of the participants, 20% achieved an objective response, including two complete responses, indicating that this combination therapy may provide clinical benefits and warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-escalation stage of a multicentre, open-label, phase 1a/b trial. Friedlander, M., Meniawy, T., Markman, B., et al.[2020]

References

1. Germany pubmed.ncbi.nlm.nih.gov

RNA interference of PARG could inhibit the metastatic potency of colon carcinoma cells via PI3-kinase/Akt pathway. [2019]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Multi-Maintenance Olaparib Therapy in Relapsed, Germline BRCA1/2-Mutant High-Grade Serous Ovarian Cancer (MOLTO): A Phase II Trial. [2023]

4. Germany pubmed.ncbi.nlm.nih.gov

Evaluation of maintenance treatment with PARP inhibitors in ovarian carcinoma patients responding to platinum therapy: Use of restricted mean survival time as an index of efficacy. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Pharmacologic characterization of fluzoparib, a novel poly(ADP-ribose) polymerase inhibitor undergoing clinical trials. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Perspectives on PARP inhibitors as pharmacotherapeutic strategies for breast cancer. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Response of Breast Cancer Cells to PARP Inhibitors Is Independent of BRCA Status. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-escalation stage of a multicentre, open-label, phase 1a/b trial. [2020]