NUV-868 + Olaparib/Enzalutamide for Cancer

Recruiting at 28 trial locations

Overseen By Nuvation Bio Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Nuvation Bio Inc.

Must not be taking: CYP3A4/5 inducers, inhibitors

Disqualifiers: Pregnancy, Breastfeeding, Recent chemotherapy, others

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

Compensation: Varies

Number of Visits: 10

82 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new drug, NUV-868, taken regularly by mouth, in patients with advanced cancers. It aims to find the best dose and see if combining it with other drugs can improve treatment. The study includes patients with advanced solid tumors and a specific type of prostate cancer.

Will I have to stop taking my current medications?

The trial requires that you stop taking chemotherapy, hormonal therapy (except certain ongoing treatments), radiation, or biological anticancer therapy at least 14 days before starting the study medication. Additionally, you cannot take medications that strongly affect certain liver enzymes (CYP3A4/5) while participating in the trial.

Will I have to stop taking my current medications?

The trial requires that you stop taking chemotherapy, hormonal therapy (except certain ongoing treatments), radiation, or biological anticancer therapy at least 14 days before starting the study drug. Additionally, you cannot take medications that strongly affect certain liver enzymes (CYP3A4/5).

What data supports the effectiveness of the drug combination NUV-868 + Olaparib/Enzalutamide for cancer?

Research shows that Olaparib, when used alone, significantly improves survival in patients with certain genetic changes and advanced prostate cancer. Enzalutamide has also been effective in treating advanced prostate cancer, and combining it with other treatments has shown promise in overcoming resistance in preclinical models. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination NUV-868 + Olaparib/Enzalutamide for cancer?

Research shows that Olaparib, when used alone, significantly improves survival in patients with certain genetic changes in prostate cancer. Additionally, Enzalutamide has proven effective in treating advanced prostate cancer, and combining it with other drugs has shown promise in overcoming resistance in preclinical models. ^{1 2 3 4 5}

Is the combination of NUV-868, Olaparib, and Enzalutamide safe for humans?

Enzalutamide has been studied for safety in prostate cancer patients, showing some risks like seizures, high blood pressure, and falls. Olaparib has been used in prostate cancer treatment, but specific safety details are not provided in the available research. No specific safety data for NUV-868 is mentioned in the research provided. ^{5 6 7 8 9}

What safety information is available for Enzalutamide and Olaparib in cancer treatment?

Enzalutamide has been associated with side effects like seizures, high blood pressure, and falls, and should be stopped if a seizure occurs. Olaparib has been studied in prostate cancer, but specific safety details are not provided in the available research. ^{5 6 7 8 9}

What makes the drug NUV-868 combined with Olaparib or Enzalutamide unique for cancer treatment?

NUV-868 combined with Olaparib or Enzalutamide is unique because it targets specific pathways in cancer cells, potentially overcoming resistance to existing treatments like enzalutamide. This combination may offer a new approach for patients with advanced prostate cancer who have not responded to other therapies. ^{1 3 4 5 10}

What makes the drug NUV-868 combined with Olaparib or Enzalutamide unique for cancer treatment?

NUV-868 combined with Olaparib or Enzalutamide is unique because it targets specific pathways involved in cancer progression, potentially offering a new approach for patients who have developed resistance to existing treatments like enzalutamide. This combination may enhance the effectiveness of current therapies by addressing different mechanisms of cancer cell survival. ^{1 3 4 5 10}

Eligibility Criteria

Adults with advanced solid tumors like ovarian, pancreatic, prostate, or breast cancer who have recovered from previous cancer therapy side effects and have good bone marrow and organ function. They must not be pregnant or breastfeeding, haven't had certain treatments recently, and can't have active brain disease.

Inclusion Criteria

My advanced cancer has worsened despite treatment, or there's no effective treatment for it.

My cancer is one of the specified types: ovarian, pancreatic, prostate, or breast.

My cancer can be measured or seen on tests.

Exclusion Criteria

I haven't taken experimental drugs recently.

I haven't had cancer treatment like chemo, hormone therapy, or radiation in the last 14 days.

I am currently pregnant or breastfeeding.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Monotherapy

NUV-868 is administered at escalating dose levels until the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) is determined

28 days

Visits on Days 1, 8, and 29

Phase 1b Combination

NUV-868 is administered in combination with olaparib or enzalutamide to determine the recommended Phase 2 combination dose (RP2cD)

28 days

Visits on Days 1, 8, and 57

Phase 2 Combination

NUV-868 is administered at the RP2cD in combination with olaparib or enzalutamide to assess safety and efficacy

12 months

Every 8 weeks during the first 24 weeks, then every 12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Enzalutamide
• NUV-868
• Olaparib

Trial Overview NUV-868 is being tested alone and combined with Olaparib or Enzalutamide in patients with advanced solid tumors to find safe doses (Phase 1/1b) and test effectiveness (Phase 2). Patients take NUV-868 orally daily for 28-day cycles until they no longer benefit.

Participant Groups

Group I: Phase 2: NUV-868 Monotherapy Experimental Treatment 1 Intervention

NUV-868 will be administered at the RP2D in one arm of a randomized Phase 2 combination (NUV-868 + enzalutamide) cohort.

Group II: Phase 2 Combination: NUV-868 + Olaparib Experimental Treatment 2 Interventions

NUV-868 will be administered at the RP2cD. Olaparib will be administered at the RP2cD.

Group III: Phase 2 Combination: NUV-868 + Enzalutamide Experimental Treatment 2 Interventions

NUV-868 will be administered at the RP2cD. Enzalutamide will be administered at the RP2cD.

Group IV: Phase 1b Combination: NUV-868 + Olaparib Experimental Treatment 2 Interventions

NUV-868 will be administered at escalating dose levels in combination with olaparib until the recommended Phase 2 combination dose (RP2cD) is determined. 300 mg olaparib will be administered orally twice daily throughout the 28-day cycles of NUV-868.

Group V: Phase 1b Combination: NUV-868 + Enzalutamide Experimental Treatment 2 Interventions

NUV-868 will be administered daily at escalating dose levels in combination with enzalutamide until the RP2cD is determined. 160 mg enzalutamide will be administered orally daily throughout the 28-day cycles of NUV-868.

Group VI: Phase 1 Monotherapy Experimental Treatment 1 Intervention

NUV-868 will be administered at escalating dose levels until the maximum tolerated dose (MTD) is reached or a recommended Phase 2 dose (RP2D) is determined.

Group VII: Phase 2: Enzalutamide Monotherapy Active Control 1 Intervention

160 mg enzalutamide will be administered orally daily in one arm of a randomized Phase 2 combination (NUV-868 + enzalutamide) cohort.

Who Is Running the Clinical Trial?

Nuvation Bio Inc.

Lead Sponsor

Trials

12

Recruited

1,200+

Findings from Research

In preclinical models of metastatic castration-resistant prostate cancer, the combination of NLG207 (a HIF-1α inhibitor) and enzalutamide significantly reduced tumor volume by 93% after 3 weeks, indicating strong efficacy against enzalutamide resistance.

The addition of NLG207 enhanced the effectiveness of enzalutamide, decreasing the median tumor growth rate by 51%, suggesting that targeting both HIF-1α and androgen receptor pathways could be a promising strategy for overcoming treatment resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Activity of NLG207 (Formerly CRLX101) in Combination with Enzalutamide in Preclinical Prostate Cancer Models. Schmidt, KT., Chau, CH., Strope, JD., et al.[2022]

In the PROFOUND phase III trial, olaparib demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS) for prostate cancer patients with BRCA1/2 mutations.

These benefits were observed across various subgroups of patients, indicating olaparib's efficacy as a targeted treatment for this specific genetic profile in prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial. Mateo, J., de Bono, JS., Fizazi, K., et al.[2023]

In a phase 2 study involving 60 patients with metastatic castration-resistant prostate cancer (mCRPC), enzalutamide treatment led to a significant decline in prostate-specific antigen (PSA) levels in 45% of patients, indicating its efficacy in managing this advanced cancer.

The study found that the presence of the androgen receptor variant ARV7 was linked to primary resistance to enzalutamide, suggesting that certain androgen signaling characteristics before treatment can predict patient response to the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer. Efstathiou, E., Titus, M., Wen, S., et al.[2022]

In the Phase III PROfound study, olaparib demonstrated improved radiographic progression-free survival (rPFS) and overall survival (OS) compared to control treatments in Asian patients with metastatic castration-resistant prostate cancer, particularly in those with BRCA gene alterations.

The safety profile of olaparib in the Asian subset was consistent with the global population, showing no new safety concerns, indicating it is a well-tolerated treatment option for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib in patients with mCRPC with homologous recombination repair gene alterations: PROfound Asian subset analysis. Matsubara, N., Nishimura, K., Kawakami, S., et al.[2023]

In a phase 3 trial involving 256 patients with metastatic castration-resistant prostate cancer and specific genetic alterations, olaparib significantly improved overall survival compared to standard treatments (median 19.1 months vs. 14.7 months) with a hazard ratio of 0.69, indicating a 31% reduction in the risk of death.

Despite a substantial number of patients (66%) in the control group crossing over to olaparib after disease progression, the results still demonstrated that olaparib is an effective treatment option for patients with BRCA1, BRCA2, or ATM alterations, highlighting its potential as a targeted therapy in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. Hussain, M., Mateo, J., Fizazi, K., et al.[2022]

In a study of 233 patients with castration-resistant prostate cancer, those starting treatment with a reduced dose of enzalutamide had a significantly lower prostate-specific antigen (PSA) response rate compared to those on the standard dose (-66.3% vs. -87.4%).

The incidence of adverse events (AEs) was not significantly different between the reduced dose and standard dose groups, suggesting that starting with a lower dose does not effectively reduce the risk of AEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial dose reduction of enzalutamide does not decrease the incidence of adverse events in castration-resistant prostate cancer. Tsuzuki, S., Nakanishi, S., Tamaki, M., et al.[2021]

Enzalutamide significantly improves overall survival in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC), with a median overall survival of 32.4 months compared to 30.2 months for placebo, based on a study of 1,717 patients.

The treatment also prolongs radiographic progression-free survival and delays the need for cytotoxic chemotherapy, while maintaining a safety profile similar to previous reports, although it requires discontinuation if seizures occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. Food and Drug Administration Approval Summary: Enzalutamide for the Treatment of Patients With Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer. Ning, YM., Brave, M., Maher, VE., et al.[2021]

In a study of 137 chemo-naïve patients with metastatic castration-resistant prostate cancer, Enzalutamide (EZ) showed a significantly higher PSA response rate compared to Abiraterone (AA) in the first line of treatment (95.9% vs 67%).

Both AA and EZ had comparable toxicity rates and progression-free survival (PFS) outcomes, indicating that both treatments are effective and well-tolerated options for managing mCRPC without chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing lines of therapy in castration-resistant prostate cancer: real-life snapshot from a multicenter cohort. Ferriero, M., Mastroianni, R., De Nunzio, C., et al.[2021]

Men with advanced prostate cancer taking abiraterone have a significantly higher risk of major metabolic or cardiovascular adverse events compared to those not on the medication, with a hazard ratio of 1.77.

Enzalutamide also increases the risk of major adverse events, but to a lesser extent (hazard ratio of 1.22), and does not significantly increase the risk of minor adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of Metabolic and Cardiovascular Adverse Events With Abiraterone or Enzalutamide Among Men With Advanced Prostate Cancer. Lai, LY., Oerline, MK., Caram, MEV., et al.[2023]

Enzalutamide significantly improves overall survival and radiographic progression-free survival in men with metastatic, castration-resistant prostate cancer (mCRPC), as shown in two major randomized trials (AFFIRM and PREVAIL) involving patients who had previously undergone chemotherapy and those who were chemotherapy naive.

While enzalutamide is generally safe and effective, it can cause side effects like fatigue and has specific safety concerns, such as an increased risk of seizures and falls, particularly in older patients (≥ 75 years).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of enzalutamide in men with metastatic, castration-resistant prostate cancer. Graff, JN., Gordon, MJ., Beer, TM.[2021]

References

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

Antitumor Activity of NLG207 (Formerly CRLX101) in Combination with Enzalutamide in Preclinical Prostate Cancer Models. [2022]

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

Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer. [2022]

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

Olaparib in patients with mCRPC with homologous recombination repair gene alterations: PROfound Asian subset analysis. [2023]

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

Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. [2022]

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

Initial dose reduction of enzalutamide does not decrease the incidence of adverse events in castration-resistant prostate cancer. [2021]

7. England pubmed.ncbi.nlm.nih.gov

U.S. Food and Drug Administration Approval Summary: Enzalutamide for the Treatment of Patients With Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer. [2021]

8. Germany pubmed.ncbi.nlm.nih.gov

Managing lines of therapy in castration-resistant prostate cancer: real-life snapshot from a multicenter cohort. [2021]

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

Risk of Metabolic and Cardiovascular Adverse Events With Abiraterone or Enzalutamide Among Men With Advanced Prostate Cancer. [2023]

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

Safety and effectiveness of enzalutamide in men with metastatic, castration-resistant prostate cancer. [2021]