Study of TVB-2640 in Men With Metastatic Castration-Resistant Prostate Cancer

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.

Eligibility Criteria:
Inclusion Criteria:

* Age \>18 years.
* Diagnosis of metastatic, castration resistant prostate cancer
* Potential participant must be planning to receive Enzalutamide as their first line of therapy for castration resistant prostate cancer or have previously received up to one line of Abiraterone or an androgen receptor antagonist
* Willing to undergo a tumor biopsy prior to beginning therapy, if recent tissue samples are not available
* Willing to undergo a tumor biopsy of at least one metastatic site or primary prostate after \~4 weeks of therapy with both agents
* Participants without prior orchiectomy must be currently taking and willing to continue luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist) therapy until permanent discontinuation of study treatment
* Sexually active, fertile participants and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom with spermicide during the course of the study and for 4 months after the last dose of study treatment
* Capable of understanding and complying with the protocol requirements and must have signed the informed consent document

Exclusion Criteria:

* Any prior cytotoxic chemotherapy for hormone sensitive prostate cancer.
* 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.
* 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
* Participants with a history of seizure
* 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.

* Inability to swallow tablets.
* Use of herbal products that may decrease PSA levels within 4 weeks prior to enrollment
* Previously identified allergy or hypersensitivity to components of the study treatment formulations.
* Diagnosis of another type of cancer within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy.
* Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with participant's safety, obtaining informed consent or compliance to the study procedures.