Talazoparib + Axitinib for Advanced Kidney Cancer

Recruiting at 9 trial locations

Overseen By Ritesh Kotecha, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: PARP inhibitors, Axitinib

Disqualifiers: Pregnancy, MDS, Uncontrolled hypertension, others

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

Compensation: Varies

Number of Visits: Unknown

23 Participants Needed

Trial Summary

What is the purpose of this trial?

Researchers are doing this study to find out if the combination of the drugs axitinib and talazoparib is a safe and effective treatment for people with your previously treated advanced kidney cancer. Researchers will look for the highest dose of talazoparib that causes few or mild side effects when given in combination with a standard dose of axitinib.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have had anti-cancer therapies within 21 days before starting the trial, and you should not use certain medications like potent P-gp inhibitors close to the trial start.

What data supports the effectiveness of the drug combination Talazoparib + Axitinib for advanced kidney cancer?

Research shows that axitinib, when combined with pembrolizumab, has improved outcomes in advanced kidney cancer, including better survival rates and response rates compared to other treatments. This suggests that axitinib, as part of a combination therapy, can be effective in treating advanced kidney cancer. ^{1 2 3 4 5}

Is the combination of Talazoparib and Axitinib safe for humans?

Axitinib, used in advanced kidney cancer, has a manageable safety profile with common side effects like diarrhea, high blood pressure, and fatigue. It has been safely combined with other drugs in trials, but specific safety data for Talazoparib combined with Axitinib is not available. ^{4 6 7 8 9}

How is the drug combination of Talazoparib and Axitinib unique for advanced kidney cancer?

The combination of Talazoparib and Axitinib is unique because it combines a PARP inhibitor (Talazoparib) with a VEGFR inhibitor (Axitinib), potentially offering a novel mechanism of action by targeting both DNA repair pathways and blood vessel growth in tumors, which is different from standard treatments that typically focus on one pathway. ^{1 7 8 10 11}

Research Team

Ritesh R Kotecha

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

Adults with advanced kidney cancer that's been treated before can join this trial. They must have had specific prior treatments, no severe liver issues, and be generally well enough to do daily activities. Pregnant women or those who've had certain other cancers recently can't participate.

Inclusion Criteria

My blood counts meet the required levels and I haven't had a blood transfusion in the last 21 days.

My kidney cancer cannot be removed by surgery and has a clear cell component.

My kidneys work well enough, with a filtration rate of at least 60 ml/min.

Exclusion Criteria

I do not have unmanaged fluid buildup.

I am currently on IV antibiotics for an infection.

I cannot take pills, have allergies to talazoparib/axitinib, or have a condition affecting my gut's ability to absorb medications.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase Ib Treatment

Participants receive combination treatment of talazoparib and axitinib to determine the recommended dose and observe dose-limiting toxicity

28 days

Phase II Treatment

Participants receive the recommended dose of talazoparib and axitinib to evaluate efficacy as measured by objective response rate

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Axitinib
• Talazoparib

Trial Overview The study tests a combo of two drugs, Talazoparib and Axitinib, for safety and effectiveness in treating advanced kidney cancer. The right dose of Talazoparib with fewer side effects is being sought while using a standard dose of Axitinib.

Participant Groups

Group I: Phase Ib, Dose Level 3 Experimental Treatment 2 Interventions

3-6 participants

Group II: Phase Ib, Dose Level 2 Experimental Treatment 2 Interventions

3-6 participants

Group III: Phase Ib, Dose Level 1 Experimental Treatment 2 Interventions

3-6 participants

Group IV: Phase II, Dose Expansion Experimental Treatment 2 Interventions

Optimal Simon 2-stage Design (14 participants initially, if MTD is tolerated well then accrual will go up to 25 participants)

Axitinib is already approved in European Union, United States, United Kingdom for the following indications:

Approved in European Union as Inlyta for:

• Renal cell carcinoma

Approved in United States as Inlyta for:

• Advanced renal cell carcinoma

Approved in United Kingdom as Inlyta for:

• Advanced renal cell carcinoma

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Findings from Research

Patients with advanced renal cell carcinoma treated with pembrolizumab plus axitinib experienced a higher incidence of grade 3/4 aminotransferase elevations (22%) compared to those treated with sunitinib (7%), indicating a need for careful monitoring of liver function during treatment.

Despite the higher rates of liver enzyme elevations, most patients (96%) with significant alanine aminotransferase (ALT) increases recovered after treatment interruption, suggesting that with proper management, the adverse effects can be effectively controlled.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Management of Treatment-emergent Hepatic Toxicity in Patients with Advanced Renal Cell Carcinoma Receiving First-line Pembrolizumab plus Axitinib. Results from the KEYNOTE-426 Trial. Rini, BI., Atkins, MB., Plimack, ER., et al.[2022]

Combination therapies using immune checkpoint inhibitors, such as axitinib plus pembrolizumab, have shown improved outcomes compared to traditional sequential monotherapy in patients with metastatic renal cell carcinoma.

Phase III trials indicate that these combination regimens significantly enhance both progression-free survival and overall survival, addressing the issue of drug resistance seen with single-agent treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus axitinib combination and the paradigm change in the treatment of advanced renal cell carcinoma. Spisarová, M., Melichar, B., Vitásková, D., et al.[2021]

The combination of axitinib and pembrolizumab shows a high response rate of 73% in patients with previously untreated advanced renal cell carcinoma, indicating strong efficacy for this treatment regimen.

This finding suggests that the dual approach of targeting both tumor growth and immune response may be effective in managing advanced kidney cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib plus Pembrolizumab Is Effective in Renal Cell Carcinoma. [2019]

The combination of axitinib and pembrolizumab is tolerable and shows promising antitumor activity in patients with treatment-naive advanced renal cell carcinoma, with 73% of patients achieving an objective response.

In a study involving 52 patients, no unexpected toxicities were observed, although 65% experienced grade 3 or worse treatment-related adverse events, indicating that while the treatment is effective, it does carry some risk of significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Atkins, MB., Plimack, ER., Puzanov, I., et al.[2023]

In the phase 3 KEYNOTE-426 trial involving 861 patients, the combination of pembrolizumab and axitinib significantly improved overall survival and progression-free survival compared to sunitinib for advanced renal cell carcinoma.

While both treatment groups showed similar health-related quality of life outcomes, the time to confirmed deterioration favored sunitinib, indicating that while pembrolizumab + axitinib is more effective in extending survival, it does not significantly enhance quality of life compared to sunitinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life Analysis from KEYNOTE-426: Pembrolizumab plus Axitinib Versus Sunitinib for Advanced Renal Cell Carcinoma. Bedke, J., Rini, BI., Plimack, ER., et al.[2022]

Axitinib is an effective second-line treatment for advanced renal cell carcinoma (RCC), showing significantly prolonged median progression-free survival compared to sorafenib in the phase III AXIS trial.

The tolerability profile of axitinib is manageable, with common side effects including diarrhea, hypertension, and fatigue, making it a viable option for patients who have already received other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib: a review in advanced renal cell carcinoma. Keating, GM.[2018]

Axitinib is a newly approved targeted therapy for advanced renal cell cancer that shows greater potency in inhibiting VEGFR1-3 compared to earlier treatments, significantly improving patient outcomes based on phase II and III clinical trials.

The drug has a manageable toxicity profile and is unique in allowing for dose titration, making it a recommended standard treatment for patients who have previously undergone antiangiogenic therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib: a review of its safety and efficacy in the treatment of adults with advanced renal cell carcinoma. Gross-Goupil, M., François, L., Quivy, A., et al.[2021]

In the phase III JAVELIN Renal 101 trial, avelumab plus axitinib demonstrated significantly improved progression-free survival (PFS) of 13.9 months compared to 8.5 months for sunitinib, indicating better efficacy in treating advanced renal cell carcinoma.

The overall survival (OS) trend also favored avelumab plus axitinib, with a hazard ratio of 0.79 compared to sunitinib, although the data is still immature and requires further follow-up.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended follow-up from JAVELIN Renal 101: subgroup analysis of avelumab plus axitinib versus sunitinib by the International Metastatic Renal Cell Carcinoma Database Consortium risk group in patients with advanced renal cell carcinoma. Haanen, JBAG., Larkin, J., Choueiri, TK., et al.[2023]

In a study of 143 patients with advanced renal cell carcinoma (RCC), over 50% of patients remained on pazopanib therapy for nearly 4 months, demonstrating high persistence and compliance across both treatment-naïve and previously treated groups.

Younger age and higher comorbidity were identified as strong predictors of better persistence and compliance with pazopanib treatment, suggesting that these factors may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Persistence and compliance with pazopanib in patients with advanced renal cell carcinoma within a U.S. administrative claims database. Hackshaw, MD., Nagar, SP., Parks, DC., et al.[2023]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Characterization and Management of Treatment-emergent Hepatic Toxicity in Patients with Advanced Renal Cell Carcinoma Receiving First-line Pembrolizumab plus Axitinib. Results from the KEYNOTE-426 Trial. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus axitinib combination and the paradigm change in the treatment of advanced renal cell carcinoma. [2021]

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

Axitinib plus Pembrolizumab Is Effective in Renal Cell Carcinoma. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life Analysis from KEYNOTE-426: Pembrolizumab plus Axitinib Versus Sunitinib for Advanced Renal Cell Carcinoma. [2022]

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

Axitinib safety in metastatic renal cell carcinoma: suggestions for daily clinical practice based on case studies. [2018]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Axitinib: a review in advanced renal cell carcinoma. [2018]

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

Axitinib: a review of its safety and efficacy in the treatment of adults with advanced renal cell carcinoma. [2021]

9. England pubmed.ncbi.nlm.nih.gov

A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Extended follow-up from JAVELIN Renal 101: subgroup analysis of avelumab plus axitinib versus sunitinib by the International Metastatic Renal Cell Carcinoma Database Consortium risk group in patients with advanced renal cell carcinoma. [2023]

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

Persistence and compliance with pazopanib in patients with advanced renal cell carcinoma within a U.S. administrative claims database. [2023]