PARG Inhibitor for Advanced Cancers

Recruiting at 23 trial locations

Overseen By Oktay Kirak, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: IDEAYA Biosciences

Must not be taking: Cytotoxic chemotherapy, Radioimmunotherapy

Disqualifiers: CNS malignancy, Cardiac abnormalities, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

216 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment, IDE161 (a PARG inhibitor), for individuals with advanced or metastatic solid tumors, indicating their cancer has spread beyond its original site. The study aims to assess the safety and effectiveness of IDE161, both alone and in combination with pembrolizumab. It seeks participants who have tried other treatments without success or experienced significant side effects. Eligible participants should have specific genetic markers related to cancer, such as BRCA1/2, or have progressed on treatments like anti-PD-1/L1 therapy. Those with advanced cancer that has spread and who have not found success with standard treatments may consider this trial. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that IDE161 has promising safety results from early studies. Researchers are testing IDE161 alone and with pembrolizumab, a drug that helps the immune system fight cancer. Early findings indicate that IDE161 is well-tolerated, meaning people can take it without serious problems, and the drug's concentration in the body matches successful lab tests.

As this is a Phase 1 trial, the main goal is to find the best dose and check for any side effects. This marks the first time IDE161 is being tested in humans, so researchers are still gathering safety information. However, the FDA has granted IDE161 a fast track designation for certain types of breast cancer, suggesting it has potential benefits and a reasonable safety profile.

For those considering joining the trial, it's important to know that researchers are closely monitoring IDE161 for any side effects to confirm its safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

IDE-161 is unique because it targets poly(ADP-ribose) glycohydrolase (PARG), offering a fresh mechanism of action compared to standard treatments for advanced cancers, which often include chemotherapy, radiation, or traditional immunotherapy. Unlike these options, IDE-161 aims to disrupt cancer cell repair pathways, potentially leading to more effective cell death. Researchers are excited about IDE-161, especially in combination with pembrolizumab, as it may enhance the immune system's ability to attack cancer cells more efficiently. This novel approach could pave the way for new treatment strategies, particularly for cancers that are resistant to existing therapies.

What evidence suggests that this trial's treatments could be effective for advanced cancers?

Research shows that IDE161, a new type of drug, may help treat certain cancers. Early results indicate that some patients with a specific genetic issue affecting DNA repair experienced tumor shrinkage. Lab studies have demonstrated that IDE161 can effectively target cancer cells in certain situations. In this trial, some participants will receive IDE161 with pembrolizumab, a drug that helps the immune system fight cancer. This combination attacks cancer cells in a new way by interfering with their repair processes. Although more research is needed, these early findings offer hope for treating advanced cancers. ^{2 3 5 6 7}

Who Is on the Research Team?

Darrin Beaupre, MD,PhD

Principal Investigator

IDEAYA Biosciences

Are You a Good Fit for This Trial?

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.

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

My cancer has a genetic change linked to DNA repair issues.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• IDE-161

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

Inhibition of PARG in colon carcinoma cells reduces their ability to invade and migrate, as shown by experiments using RNA interference and a mouse model of liver metastasis.

The suppression of metastatic behavior is linked to the activation of the PI3K/Akt signaling pathway, while also decreasing levels of NF-κB and matrix metalloproteinases (MMP2 and MMP9), indicating a potential therapeutic target for reducing metastasis in colon cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RNA interference of PARG could inhibit the metastatic potency of colon carcinoma cells via PI3-kinase/Akt pathway. Li, Q., Li, M., Wang, YL., et al.[2019]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05787587

NCT05787587 | A Study of PARG Inhibitor IDE161 in ... The purpose of this study is to characterize the safety, tolerability, and efficacy of IDE161 as a single agent and in combination with pembrolizumab. Detailed ...

2. trialx.com trialx.com/clinical-trials/listings/218682/a-study-of-parg-inhibitor-ide161-in-participants-with-advanced-solid-tumors/?&radius=50

A Study of PARG Inhibitor IDE161 in Participants With ... The purpose of this study is to characterize the safety, tolerability, and efficacy of IDE161 as a single agent and in combination with ...

3. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/402215

A Study of PARG Inhibitor IDE161 in Participants With ... The purpose of this study is to characterize the safety, tolerability, and efficacy of IDE161 as a single agent and in combination with pembrolizumab.

4. prnewswire.com prnewswire.com/news-releases/ideaya-announces-first-patient-in-for-phase-1-clinical-trial-evaluating-ide161-in-combination-with-keytruda-pembrolizumab-in-patients-with-endometrial-cancer-302326988.html

IDEAYA Announces First-Patient-In for Phase 1 Clinical ... IDE161 is a potential first-in-class inhibitor of poly(ADP-ribose) glycohydrolase (PARG), a novel, mechanistically distinct target in the same ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05787587?cond=(BREAST%20CANCER)%20OR%20(AKT1%20OR%20XRCC3%20OR%20TP53%20OR%20BRIP1%20OR%20PHB1%20OR%20CASP8%20OR%20HMMR%20OR%20KRAS%20OR%20CDH1%20OR%20PIK3CA%20OR%20ESR1%20OR%20RAD51%20OR%20BARD1%20OR%20RB1CC1%20OR%20RAD54L%20OR%20ATM%20OR%20SLC22A1L%20OR%20PPM1D%20OR%20NQO2%20OR%20BRCA2)&rank=10

A Study of PARG Inhibitor IDE161 in Participants With ... The purpose of this study is to characterize the safety, tolerability, and efficacy of IDE161 as a single agent and in combination with pembrolizumab. Detailed ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05787587

NCT05787587 | A Study of PARG Inhibitor IDE161 in ... The purpose of this study is to characterize the safety, tolerability, and efficacy of IDE161 as a single agent and in combination with pembrolizumab. Detailed ...

7. cancer.gov cancer.gov/clinicaltrials/NCI-2023-03139

A Study of PARG Inhibitor IDE161 in Participants With ... The purpose of this study is to characterize the safety, tolerability, and efficacy of IDE161 as a single agent and in combination with pembrolizumab.