NUV-868 as Monotherapy and in Combination With Olaparib or Enzalutamide in Adult Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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NUV-868-01 is a first-in human, open- label, Phase 1/2 dose escalation and expansion study in patients with advanced solid tumors. The Phase 1 and 1b portions include patients with advanced solid tumors and are designed to determine the safety and the dose(s) of NUV-868 to be used as monotherapy and in combination with olaparib or enzalutamide for the Phase 2 portion. In Phase 2, NUV-868 in combination with olaparib or enzalutamide will be given to determine the safety and efficacy of these study treatments. One cohort of patients (with enzalutamide-naïve metastatic castration-resistant prostate cancer) will be randomized to receive either NUV-868 monotherapy, enzalutamide monotherapy, or the combination of NUV-868 + enzalutamide. Patients will self-administer NUV-868 orally daily in 28-day cycles as monotherapy in Phases 1 and 2. In Phases 1b and 2, patients will self-administer NUV-868 orally daily in 28-day cycles in combination with olaparib or enzalutamide daily at standard prescribed doses (Phase 1b) or at the recommended Phase 2 combination dose (RP2cD) that is determined in Phase 1b. Patients will be treated until disease progression, toxicity, withdrawal of consent, or termination of the study.

Official Title
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Phase 1/2 Safety and Efficacy Study of NUV-868 as Monotherapy and in Combination With Olaparib or Enzalutamide in Adult Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor, Ovarian Cancer, Ovary Cancer, Cancer of Ovary, Cancer of the Ovary, Ovary Neoplasm, Pancreatic Cancer, Pancreas Cancer, Cancer of Pancreas, Cancer of the Pancreas, Pancreas Neoplasm, Prostate Cancer, Prostatic Cancer, Cancer of Prostate, Cancer of the Prostate, Prostate Neoplasm, Castrate Resistant Prostate Cancer, Castration Resistant Prostatic Cancer, Castration Resistant Prostatic Neoplasms, Triple-negative Breast Cancer, Triple Negative Breast Cancer, Triple Negative Breast Neoplasms, Breast Cancer, Breast Carcinoma, Cancer of Breast, Cancer of the Breast, Breast Tumor

Intervention / Treatment
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* Drug: NUV-868
* Drug: Olaparib
* Drug: Enzalutamide


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria For All Phases and Cohorts: Recovered from toxicity to prior anticancer therapy Adequate bone marrow and organ function No known active or symptomatic central nervous system (CNS) disease Cohort-Specific Inclusion Criteria: In addition to the inclusion criteria listed above, the following criteria apply for enrollment into specific cohorts. Phase 1 (NUV-868 Monotherapy) Patients with advanced solid tumors that have progressed during or after treatment with approved therapies or for which there is no standard effective therapy available Life expectancy of > 3 months Eastern Cooperative Oncology Group Performance Status ≤ 2 Measurable or non-measurable disease Phase 1b (NUV-868 in Combination With Enzalutamide or Olaparib) Life expectancy of > 3 months Eastern Cooperative Oncology Group Performance Status ≤ 2 (Select cohorts only) Measurable disease Patient must be able to read and write sufficiently to document food intake and study drug dosing on the Dosing Diary or must have a caregiver who is willing and able to complete the Dosing Diary with the patient. One of the following tumor types: Ovarian: Platinum-resistant OR platinum-refractory high grade serous ovarian, fallopian, or primary peritoneal cancer in the relapsed setting Pancreatic: Pancreatic ductal adenocarcinoma (PDAC) with progression on or after treatment with at least one line of systemic chemotherapy in the advanced setting Prostate: Histologically confirmed, metastatic adenocarcinoma of the prostate (adenocarcinoma/high grade carcinoma with neuroendocrine features is allowed) with progression on or after treatment with at least one NHT in the metastatic setting Breast: Triple-negative breast cancer (TNBC) with progression on or after treatment with at least one line of systemic chemotherapy in the advanced setting Other advanced tumors (only Phase 1b dose escalation, NUV-868 + olaparib): the study Medical Monitor must approve enrollment. For all tumor types: Patients will be allowed in the study regardless of their BRCA/HRR status. Phase 2 Life expectancy of > 6 months (Select cohorts only): At least one measurable lesion defined by standard criteria Eastern Cooperative Oncology Group Performance Status ≤ 1 One of the following tumor types: Ovarian: Platinum-resistant or platinum- refractory high grade serous ovarian, fallopian, or primary peritoneal cancer in the relapsed setting Pancreatic: Progression on or after treatment with at least one line of systemic chemotherapy in the advanced setting Prostate: Histologically confirmed, metastatic adenocarcinoma of the prostate (adenocarcinoma/high grade carcinoma with neuroendocrine features is allowed) with progression on or after treatment with at least one NHT in the metastatic setting Breast: TNBC with progression on or after treatment with at least one line of systemic chemotherapy in the advanced setting Key Exclusion Criteria For All Phases and Cohorts: Have received chemotherapy, hormonal therapy (except for ongoing luteinizing hormone-releasing hormone [LHRH] analogs in male patients and premenopausal women), radiation, or biological anticancer therapy within 14 days prior to the first dose of NUV-868. Received treatment with an investigational agent for any indication within 14 days for non-myelosuppressive agent, or within 21 days or < 5 half-lives (whichever is longer) for myelosuppressive agent, prior to the first dose of study treatment. Requires medications that are known to be strong (or moderate for olaparib) inducers and/or strong (or moderate for olaparib) inhibitors of CYP3A4/5 enzymes. Female patients who are pregnant of breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Sequential assignment will be applied in Phase 1 and Phase 1 b dose escalation cohorts. Parallel assignment will be applied in Phase 1b backfill cohorts and Phase 2.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Monotherapy<br>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. | Drug: NUV-868<br>* NUV-868 is an investigational drug for oral dosing.<br>|
| Experimental: Phase 1b Combination: NUV-868 + Olaparib<br>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. | Drug: NUV-868<br>* NUV-868 is an investigational drug for oral dosing.<br>Drug: Olaparib<br>* Olaparib<br>* Other names: Lynparza;|
| Experimental: Phase 1b Combination: NUV-868 + Enzalutamide<br>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. | Drug: NUV-868<br>* NUV-868 is an investigational drug for oral dosing.<br>Drug: Enzalutamide<br>* Enzalutamide<br>* Other names: Xtandi;|
| Experimental: Phase 2 Combination: NUV-868 + Olaparib<br>NUV-868 will be administered at the RP2cD. Olaparib will be administered at the RP2cD. | Drug: NUV-868<br>* NUV-868 is an investigational drug for oral dosing.<br>Drug: Olaparib<br>* Olaparib<br>* Other names: Lynparza;|
| Experimental: Phase 2 Combination: NUV-868 + Enzalutamide<br>NUV-868 will be administered at the RP2cD. Enzalutamide will be administered at the RP2cD. | Drug: NUV-868<br>* NUV-868 is an investigational drug for oral dosing.<br>Drug: Enzalutamide<br>* Enzalutamide<br>* Other names: Xtandi;|
| Experimental: Phase 2: NUV-868 Monotherapy<br>NUV-868 will be administered at the RP2D in one arm of a randomized Phase 2 combination (NUV-868 + enzalutamide) cohort. | Drug: NUV-868<br>* NUV-868 is an investigational drug for oral dosing.<br>|
| Active Comparator: Phase 2: Enzalutamide Monotherapy<br>160 mg enzalutamide will be administered orally daily in one arm of a randomized Phase 2 combination (NUV-868 + enzalutamide) cohort. | Drug: Enzalutamide<br>* Enzalutamide<br>* Other names: Xtandi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 Monotherapy Dose Escalation: Safety and tolerability of NUV-868 to determine the recommended Phase 2 dose (RP2D) | Incidence of dose-limiting toxicities (DLTs) | During the DLT period (28 days) | 
| Phase 1b Dose Escalation, NUV-868 + Olaparib: Safety and tolerability of NUV-868 in combination with olaparib to determine the recommended Phase 2 combination dose (RP2cD) | Incidence of DLTs | During the DLT period (28 days) | 
| Phase 1b Dose Escalation, NUV-868 + Olaparib: Pharmacokinetic (PK) profiles of NUV-868 and olaparib when administered in combination | NUV-868 and olaparib combination PK | Days 1, 8, and 29 | 
| Phase 1b Dose Escalation, NUV-868 + Enzalutamide: Safety and tolerability of NUV-868 in combination with enzalutamide to determine the RP2cD | Incidence of DLTs | During the DLT period (28 days) | 
| Phase 1b Dose Escalation, NUV-868 + Enzalutamide: Pharmacokinetic (PK) profiles of NUV-868 and enzalutamide when administered in combination | NUV-868 and enzalutamide combination PK | Days 1, 8, and 57 | 
| Phase 2, NUV-868 + Olaparib: Change from Baseline in Tumor Imaging | ORR per standard criteria | Every 8 weeks during the first 24 weeks and then every 12 weeks, up to an average of 12 months (end of treatment) | 
| Phase 2, NUV-868 + Olaparib: Change from Baseline in PSA measurements | PSA50 response rate per standard criteria; only for patients with prostate cancer | Every 4 weeks throughout study treatment, up to an average of 12 months (end of treatment) | 
| Phase 2, NUV-868 + Enzalutamide in Enzalutamide-Naïve Metastatic Castrate-Resistant Prostate Cancer (mCRPC): Time from First Dose to Disease Progression | Radiographic progression-free survival (rPFS) per standard criteria | Every 8 weeks during the first 24 weeks and then every 12 weeks, up to an average of 12 months (end of treatment) | 
| Phase 2, NUV-868 + Enzalutamide in Enzalutamide-Resistant mCRPC: Response to Study Treatment | Composite response rate (CRR: radiologic response, PSA50 response, and/or circulating tumor cell response) per standard criteria | Every 4-12 weeks (time points vary depending on the type of response being evaluated) throughout study treatment, up to an average of 12 months (end of treatment) | 
| Phase 1b Food Effect Substudy: Effect of Food on the Pharmacokinetics (PK) of NUV-868 | NUV-868 PK parameters in fed and fasted states | Pre dose and 24 hours after the first and second doses of NUV-868, 7 days apart | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, Phase 2, NUV-868, olaparib, enzalutamide, Xtandi, ovarian cancer, pancreatic cancer, metastatic castration-resistant prostate cancer, triple-negative breast cancer, Lynparza, PARP inhibitor, BET inhibitor, BRCA mutation, BRCA1, BRCA2, HRD, HRR deficiency, homologous recombination deficiency