Phase 1 First in Human Trial to Assess Safety and Tolerability of the Novel ACK1 Inhibitor (R)-9b in Patients With Prostate Cancer
Objective: To assess the safety and tolerability of (R)-9bMS in patients with metastatic castration-resistant prostate cancer. Secondary
Objectives: To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of (R)-9bMS in patients with CRPC. To determine the pharmacokinetics (PK) of (R)-9bMS in patients after single and multiple dose oral administration. To assess clinical outcomes and anti-tumor activity in patients treated with (R)-9bMS. ENDPOINTS: Primary Endpoint: Frequency of dose-limiting toxicities and toxicity and severe AEs per CTCAE v 5.0. Secondary Endpoints: * RP2D (recommended phase 2 dose) * PK (pharmacokinetics) * PSA responses * Duration of responses * ORR (objective response rate) * OS (overall survival) * PFS (progression free survival) * DSS (disease specific survival) * Toxicity and severe AEs per CTCAE v 5.0 STUDY POPULATION: Approximately 18-30 adult patients with a histologic or cytologic diagnosis of metastatic castration resistant prostate cancer will be enrolled. PHASE: Phase I DESCRIPTION OF SITES: This study will be open to enrollment at the University of Wisconsin Carbone Cancer Center DESCRIPTION OF STUDY INERVENTION: (R)-9bMS will be taken by mouth twice daily until completion of 12 cycles, progression or intolerance STUDY DURATION: 12 months for enrollment + 12 months treatment + 12 months follow-up + 12 months for data analysis = 48 months.
• Histologically or cytologically confirmed prostate cancer (mCRPC).
• Must have evidence of metastatic disease on conventional imaging (eg. CT, MRI, technetium bone scan). May have any type or location of metastases (bone, lymph node, visceral). RECIST 1.1 measurable disease is not required; may have bone-only metastases.
• Ongoing androgen deprivation therapy (ADT) at time of study enrollment (GnRHR agonist such as leuprolide, goserelin, triptorelin, buserelin, histrelin; GnRHR antagonists such as degarelix or relugolix), or history of surgical castration.
• Must have evidence of castrate testosterone levels with baseline serum testosterone level of 50 ng/dL or less at time of study start, and castrate levels should be maintained throughout study.
• Evidence of progressive castration-resistant prostate cancer, defined as at least 2 consecutive rises of PSA, at least 1 week apart with the last PSA ≥ 2 ng/mL or by evidence of radiographic progression.
• Patients must have had prior disease progression on at least one novel hormonal agent (NHA) (eg enzalutamide, abiraterone, apalutamide, darolutamide, etc.); treatment with NHA could have occurred in the castration-sensitive or castration-resistant setting.
• Prior palliative radiation therapy for bone metastasis (must be complete ≥ 14 days prior to enrollment) or any other radiation therapy (must be complete ≥ 28 days prior to enrollment) is allowed. Prior definitive radiation therapy for localized prostate cancer is allowed.
• Recovery to baseline or ≤ grade 1 from toxicities related to any prior treatments, unless AEs are clinically nonsignificant and/or stable on supportive therapy.
• At least 18 years of age.
⁃ ECOG performance status ≤ 1
⁃ Normal bone marrow and organ function as defined below:
∙ Absolute neutrophil count ≥ 1,500/mm3 without granulocyte colony-stimulating factor support
‣ White blood cell count ≥ 2,000/mm3
‣ Platelets ≥ 100,000/mm3 without transfusion
‣ Hemoglobin ≥ 9.0 g/DL
‣ Total bilirubin ≤ 1.5 x IULN (for subjects with Gilbert's disease ≤ 3.0 x IULN)
‣ AST(SGOT), ALT(SGPT) ≤ 3.0 x IULN
‣ Serum creatinine ≤ 1.5 x IULN or calculated creatinine clearance ≥ 45 mL/min by Cockcroft-Gault
‣ Serum albumin ≥ 2.8 g/dL
‣ Urine protein/creatinine ration (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) (only evaluated if creatinine abnormal per criteria above
‣ PT/INR or PTT \< 1.5 x IULN (PT/INR must be drawn \< 7 days prior to biopsy for those patients treated in MTD cohort), unless participant is receiving anticoagulant therapy and these are within intended therapeutic ranges for anticoagulant.
⁃ Corrected QT interval calculated by the Fridericia formula (QTcF) ≤ 500 ms (by ECG).
⁃ Ability to understand and willingness to sign an IRB approved written informed consent document (or that of the legally authorized representative, if applicable).
⁃ Willingness and ability to undergo biopsy for research component of the trial (for patients treated in MTD cohort)
⁃ Heterosexually active male patients (along with their female partners) are required to use two forms of acceptable contraception, including one barrier method, during participation in the study and for 5 months following the last day of study treatment. If a female partner of a male patient becomes pregnant during therapy or within 5 months after the last day of study treatment, the investigator must be notified in order to facilitate outcome follow-up.