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| Name | Class |
|---|---|
| Sagimet Biosciences Inc. | INDUSTRY |
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The purpose of this study is to determine what effects (good and bad) Enzalutamide and TVB-2640 have in the treatment of prostate cancer whose prostate cancer has spread to other parts of their body and that has not gotten better with previous treatment. This study is a Phase I clinical trial. Phase I clinical trials test the side effects of an investigational drug or an investigational combination with another drug. "Investigational" means that the drug is still being studied and research doctors are trying to find out more about it. Although Enzalutamide is already being used to treat men with prostate cancer, combining Enzalutamide with TVB-2640 together in patients with prostate cancer is considered experimental. This research study is being done because additional effective treatments are needed for prostate cancer that has spread and is growing despite hormone suppression. By doing this study, the investigators hope to learn if combining Enzalutamide with TVB-2640 can be done safely. Participation in this research will last about 12 to 24 months after enrollment.
This phase I, open-label, dose-escalation study is designed to evaluate the dose limiting toxicities (DLTs) and maximum-tolerated dose (MTD) of TVB-2640 plus Enzalutamide and establish the TVB-2640 dose recommended for further investigation in phase 2 (i.e., recommended phase 2 dose [RP2D]). Patients with a confirmed histological or cytological diagnosis of prostate cancer (PC), evidence of metastatic PC on imaging (bone scan and/or CT/MRI scan), serum testosterone <50 ng/dl, who had progressed on androgen-depletion therapy (ADT), with documented progressive metastatic castration-resistant prostate cancer (mCRPC) based on Prostate Cancer Working Group 3 (PCWG3) criteria and no previously treatment with cytotoxic chemotherapy are eligible. This study represents the first clinical evaluation of TVB-2640 in combination with Enzalutamide. All patients will receive Enzalutamide monotherapy at the approved dose of 160 mg once daily for 28 days to reach the steady state as determined by measuring Enzalutamide and des-methyl-Enzalutamide levels. Participants who complete the Enzalutamide run-in period will begin oral TVB-2640 at the dose of 100 mg. The dose escalation scheme will be the Bayesian optimal interval (BOIN) design with additional dose levels of 100 mg, 150mg, 200 mg, 250 mg, and 300mg daily. The maximum sample size for the phase I will be 30 patients and the target DLT rate is 25% or less and a maximum of 9 patients at any dose level.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| TVB-2640 in combination with Enzalutamide | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TVB-2640 | Drug | TVB- 2640 at 100 mg, 150mg, 200 mg, 250 mg, or 300mg daily, orally; dose determined by BOIN dose escalation per the protocol |
|
| Measure | Description | Time Frame |
|---|---|---|
| Optimal dose of TVB-2640 in combination with Enzalutamide, as determined by the maximum tolerated dose (MTD) | The maximum tolerated dose (MTD) is defined as the highest dose level at which ≤1 patient experiences a dose-limiting toxicity, as defined in the protocol (DLT). Once all the patients are accrued, the MTD will be determined by performing isotonic regression on the pooled data. | Day 28 |
| Measure | Description | Time Frame |
|---|---|---|
| Number of adverse events (evaluated using the NCI CTCAE v5.0) of different doses of TVB-2640 in combination with Enzalutamide | All observed AEs will be tabulated and reported as relative frequencies (i.e., fraction of patients with that AE). This will be done by AE and maximum grade experienced within a patient. The fraction of patients with each AE by grade will be estimated with a binomial point estimate and corresponding 95% binomial confidence interval (CI). AEs will be collected until 30 days following the last dose of study drug. AEs will be reported for each different dose of TVB-2640 given. |
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Inclusion Criteria:
Exclusion Criteria:
Receipt of any type of biologic, or other systemic anticancer therapy (including investigational) except agents within 4 weeks before first dose of study treatment. Anti-resorptive bone agents are also allowed.
Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. Participants with clinically relevant ongoing complications from prior radiation therapy are not eligible.
Prior exposure to taxane chemotherapy
History of pneumonitis
Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to first dose of study treatment after major surgery (e.g., removal or biopsy of brain metastasis). Participants must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Eligible participants must be neurologically asymptomatic and without corticosteroid treatment for neurological indications at the time of first dose of study treatment.
Participants with clinically significant dry eye or corneal abnormalities
Currently taking certain anticoagulation medications, such as coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel)
Participant has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 1.3 X the laboratory ULN within 30 days before the first dose of study treatment.
Participants should not receive strong CYP2C8 or strong P-gp inhibitors; strong CYP3A4 or CYP2C8 inducers; and strong CYP3A4, CYP2C9 and CYP2C19 substrates while participating in the trial, unless utilized with caution to treat a drug-related AE when no alternative is available and discussed with the Medical Monitor.
Participant has uncontrolled, significant intercurrent or recent Cardiovascular disorders including, but not limited to, the following conditions:
i. Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.
ii. Uncontrolled hypertension defined as sustained blood pressure (BP) >140 mm Hg systolic or >90 mm Hg diastolic despite optimal antihypertensive treatment.
iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g. deep venous thrombosis, pulmonary embolism) within 6 months before first dose.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| GUONC Research Team | Contact | 646-962-2072 | guonc@med.cornell.edu | |
| Escarleth Fernandez | Contact | 646-962-9406 | esf4001@med.cornell.edu |
| Name | Affiliation | Role |
|---|---|---|
| David Nanus, M.D. | Weill Medical College of Cornell University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Weill Cornell Medicine/NewYork-Presbyterian Hospital | Recruiting | New York | New York | 10021 | United States |
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| ID | Term |
|---|---|
| D064129 | Prostatic Neoplasms, Castration-Resistant |
| ID | Term |
|---|---|
| D011471 | Prostatic Neoplasms |
| D005834 | Genital Neoplasms, Male |
| D014565 | Urogenital Neoplasms |
| D009371 | Neoplasms by Site |
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| ID | Term |
|---|---|
| C000717092 | TVB-2640 |
| C540278 | enzalutamide |
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| Enzalutamide | Drug | 160 mg daily PO |
|
|
| 12 months |
| Mean TVB-2640 total exposure (as measured by the area under the drug serum concentration vs. the time from administration curve [AUC]) | Peripheral blood will be drawn at: Day 28:
Days 36-37:
Days 43-44:
Days 50-51:
| Day 28; Days 36-37; Days 43-44; Days 50-51 |
| Mean Enzalutamide total exposure (as measured by the area under the drug serum concentration vs. the time from administration curve [AUC]) | Peripheral blood will be drawn at: Day 28:
Days 36-37:
Days 43-44:
Days 50-51:
| Day 28; Days 36-37; Days 43-44; Days 50-51 |
| Mean maximum serum concentration (Cmax) of TVB-2640 | Peripheral blood will be drawn at the following times: Day 28:
Days 36-37:
Days 43-44:
Days 50-51:
| Day 28; Days 36-37; Days 43-44; Days 50-51 |
| Mean maximum serum concentration (Cmax) of Enzalutamide | Peripheral blood will be drawn at the following times: Day 28:
Days 36-37:
Days 43-44:
Days 50-51:
| Day 28; Days 36-37; Days 43-44; Days 50-51 |
| Mean minimum serum concentration (Cmin) of TVB-2640 | Peripheral blood will be drawn at the following times: Day 28:
Days 36-37:
Days 43-44:
Days 50-51:
| Day 28; Days 36-37; Days 43-44; Days 50-51 |
| Mean minimum serum concentration (Cmin) of Enzalutamide | Peripheral blood will be drawn at the following times: Day 28:
Days 36-37:
Days 43-44:
Days 50-51:
| Day 28; Days 36-37; Days 43-44; Days 50-51 |
| Mean TVB-2640 volume of distribution at steady state | Peripheral blood will be drawn at the following times: Day 28:
Days 36-37:
Days 43-44:
Days 50-51:
| Day 28; Days 36-37; Days 43-44; Days 50-51 |
| Mean Enzalutamide volume of distribution at steady state | Peripheral blood will be drawn at the following times: Day 28:
Days 36-37:
Days 43-44:
Days 50-51:
| Day 28; Days 36-37; Days 43-44; Days 50-51 |
| Mean time to maximum TVB-2640 serum concentration (Tmax) after administration | Peripheral blood will be drawn at the following times: Day 28:
Days 36-37:
Days 43-44:
Days 50-51:
| Day 28; Days 36-37; Days 43-44; Days 50-51 |
| Mean time to maximum Enzalutamide serum concentration (Tmax) after administration | Peripheral blood will be drawn at the following times: Day 28:
Days 36-37:
Days 43-44:
Days 50-51:
| Day 28; Days 36-37; Days 43-44; Days 50-51 |
| Mean Serum half-life (T1/2) of TVB-2640 | Peripheral blood will be drawn at the following times: Day 28:
Days 36-37:
Days 43-44:
Days 50-51:
| Day 28; Days 36-37; Days 43-44; Days 50-51 |
| Mean Serum half-life (T1/2) of Enzalutamide | Peripheral blood will be drawn at the following times: Day 28:
Days 36-37:
Days 43-44:
Days 50-51:
| Day 28; Days 36-37; Days 43-44; Days 50-51 |
| Mean TVB-2640 clearance | Peripheral blood will be drawn at the following times: Day 28:
Days 36-37:
Days 43-44:
Days 50-51:
| Day 28; Days 36-37; Days 43-44; Days 50-51 |
| Mean Enzalutamide clearance | Peripheral blood will be drawn at the following times: Day 28:
Days 36-37:
Days 43-44:
Days 50-51:
| Day 28; Days 36-37; Days 43-44; Days 50-51 |
| Prostate-Specific Antigen (PSA) Response Rate | The PSA response rate will be evaluated using PCWG3 criteria and defined as the proportion of patients with a PSA decline of at least 50%. Any change from baseline is confirmed by a second measurement at least 3 weeks later. PSA Response Rate will be evaluated using PCWG3 criteria and defined as following: Percentage change from baseline in PSA to 12 weeks post Enzalutamide plus TVB-2640. Only evaluate for patients with at least 12 weeks of treatment, the PSA assessment at 12 weeks (84 days +/-3 days) will be used; Maximum percent decrease in PSA from baseline that occurs at any point after treatment. | Baseline; 12 weeks |
| Overall radiographic response rate | Tumor response will be evaluated using the PCWG3 criteria. Patients with measurable disease will be evaluated for clinical benefit as determined by tumor response using RECIST v1.1. Patients with non-measurable bone disease will be evaluated for progression based on the presence of any new lesions by bone scans. Radiographic tumor evaluation will be performed at screening and every 3 cycles or more frequently as determined by the investigator. Using the tumor response that is determined by the investigator, best overall response will be determined using RECIST v1.1. Best overall response is defined as the best response recorded from the start of treatment until disease progression or study exit. The overall response rate will be determined as the number of patients with a confirmed PR or CR divided by the total number of patients evaluable for overall response. | From baseline until disease progression for a maximum of 2 years from enrollment |
| Overall median progression free survival (PFS) | Overall progression free survival (PFS) is determined using the PCWG3 criteria. Overall PFS is measured from screening until the time that disease progression (radiographic progressive disease or clinical deterioration) or death is documented, whichever occurs first. | From baseline until disease progression or death from any cause for a maximum of 2 years from enrollment |
| Median radiographic progression free survival (PFS) as assessed by PCWG3 | Radiographic progression-free survival (rPFS) is determined using the PCWG3 criteria to assess both soft-tissue and bone assessments. The rPFS is measured from screening until the time the first radiographic scan shows disease progression, or until the time of death, whichever occurs first. Patients who do not progress radiographically or did not die prior to study exit are censored on the date of their last dose of Enzalutamide plus TVB-2640. PFS will be summarized with a Kaplan-Meier curve. The Kaplan-Meier estimator will be used to determine the 6-month and 12-month PFS rates. Each estimate will have a corresponding 95% confidence interval. The median PFS will also be estimated with a corresponding 95% confidence interval | From baseline until disease progression for a maximum of 2 years from enrollment |
| D009369 |
| Neoplasms |
| D005832 | Genital Diseases, Male |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D011469 | Prostatic Diseases |
| D052801 | Male Urogenital Diseases |