Novel ACK1 Inhibitor (R)-9b in Patients With Prostate Cancer

NCT06705686 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: CA2864431R01CA286443-01A1
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

TITLE: Phase 1 First in Human Trial to Assess Safety and Tolerability of the Novel ACK1 Inhibitor (R)-9bMS in Patients with Prostate Cancer (PHAROS) STUDY DESCRIPTION: Prostate cancer (PC) patients receive androgen deprivation therapy (ADT), but recalcitrant disease recurs typically within 2-3 years, referred to as the Castration Resistant Prostate Cancer (CRPC). Androgen receptor (AR) targeted therapies, such as Enzalutamide (Enz) or Abiraterone (Abi), are FDA-approved therapeutics for CRPC patients. However, virtually all patients develop resistance. A non-receptor tyrosine kinase, ACK1 act as a novel epigenetic modifier in prostate tumors, regulating AR and its splice variant, AR-V7 expression. A new class of ACK1 small molecule inhibitor, (R)-9bMS, was developed that exhibited excellent drug-like properties. Treatment with (R)-9bMS suppressed Abi and Enz-resistant tumor growth in mice. Robust immune activation against prostate tumors was also reflected in mice treated with ACK1 inhibitor, (R)-9bMS. Importantly (R)-9bMS functionally reinvigorated peripheral blood mononuclear cells (PBMCs) of CRPC patients to mount a robust immune response against CRPC organoids. Collectively, these data indicate that the ACK1 inhibitor, (R)-9bMS, fulfills a unique niche, wherein it not only suppressed AR/AR-V7 within the tumor milieu, but also activated host immune system by overcoming CSK-restrained LCK activity, to mount a robust 'dual' anti-tumor response. OBJECTIVES: Primary 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.

Conditions

Metastatic Castration-resistant Prostate Cancer (CRPC); Metastatic Castration-resistant Prostate Carcinoma

Keywords

ACK1; TNK2; Non-receptor tyrosine kinase; small molecule inhibitor; prostate cancer; CRPC; kinase inhibitor; Androgen receptor antagonist; Immune modulator

Outcome Measures

Primary Outcomes (1)

• Frequency of dose-limiting toxicities (Dose Escalation only)

  Dose-limiting toxicities are defined in the protocol.

  From day 1 of treatment through day 28 of treatment

Secondary Outcomes (4)

• Recommended phase 2 dose (RP2D) (Dose Escalation only)

  From day 1 of treatment through day 28 of treatment

• Number of patients with a prostate specific antigen (PSA) response

  From baseline through end of treatment (up to 6 months)

• Overall response rate (ORR)

  From baseline through end of treatment (up to 12 months)

• Progression-free survival (PFS)

  From start of treatment through the completion of follow-up (up to 24 months)

Study Arms (2)

Dose Escalation: (R)-9bMS

EXPERIMENTAL

Patient will take the assigned dose of (R)-9bMS twice daily by mouth for up to 6 months. Each cycle is 28 days.

Drug: (R)-9bMS

Expansion: (R)-9bMS

EXPERIMENTAL

Patient will take (R)-9bMS twice daily by mouth for up to 6 months. Each cycle is 28 days. The assigned dose will be determined in the Dose Escalation portion of the trial.

Drug: (R)-9bMS

Interventions

(R)-9bMS DRUG

(R)-9bMS will be given in clinic on day 1, two doses 12 hours (+/- 30 minutes) apart, and on day 2, 12 hours (+/- 30 minutes) after the second day 1 dose. Patients will be admitted overnight for these first 3 doses. Patient must be fasting 1 hour before and 1 hour after doses for these first 3 doses. (R)-9bMS should be taken with a glass of water. Patients will be dispensed home supply after C1D2 morning dose.

Also known as: Mahatinib

Dose Escalation: (R)-9bMS; Expansion: (R)-9bMS

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 14 days before first dose of study treatment.
• Exclusively small cell variant of prostate cancer, or other prostate cancer histology that does not contain adenocarcinoma
• Inability to swallow pills.
• Presence of a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 calendar days of start of study treatment. Inhaled or topical steroids and adrenal replacement steroid doses \< 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
• Any other active malignancy at time of first dose of study treatment or diagnosis of another malignancy within 3 years prior to first dose of study treatment that requires active treatment, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, or superficial bladder cancer. Any history of prior malignancy must be reviewed by the PI.
• Currently receiving any other investigational agents.
• Any anti-androgen receptor agents or abiraterone (or similar CYP17,20 lyase inhibitor) within 14 days or 5 half-lives, whichever is longer, prior to the start of study drug.
• Use of Radium-223 or other radioligand/radiopharmaceutical within 28 days prior to the start of study drug
• Any gastrointestinal issues affecting absorption (e.g. gastrectomy, bowel resection, etc), as determined by the PI.
• Blood transfusion within 28 days of screening.
• Use of hormonal agents or supplements with potential anti-tumor activity against prostate cancer, as determined by the PI, within 28 days prior to the start of study drug.
• Bone-modifying agents (eg zolendronic acid, denosumab, etc) may not be initiated after start of study drug; previously initiated agents may be continued while on trial.
• Patients with 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). Eligible subjects must be neurologically asymptomatic.
• History of seizures or seizure disorder.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to (R)-9bMS used in the study.

Sponsors & Collaborators

• University of Wisconsin, Madison: collaborator
• TechnoGenesys, Inc.: lead
• National Cancer Institute (NCI): collaborator
• Washington University School of Medicine: collaborator

Study Sites (1)

University of Wisconsin Carbone Cancer Center (UWCCC) - Cancer Connect

Madison, Wisconsin, 53792, United States

RECRUITING

Related Publications (5)

• Sawant M, Mahajan K, Renganathan A, Weimholt C, Luo J, Kukshal V, Jez JM, Jeon MS, Zhang B, Li T, Fang B, Luo Y, Lawrence NJ, Lawrence HR, Feng FY, Mahajan NP. Chronologically modified androgen receptor in recurrent castration-resistant prostate cancer and its therapeutic targeting. Sci Transl Med. 2022 Jun 15;14(649):eabg4132. doi: 10.1126/scitranslmed.abg4132. Epub 2022 Jun 15.

  PMID: 35704598 RESULT

• Chouhan S, Sawant M, Weimholt C, Luo J, Sprung RW, Terrado M, Mueller DM, Earp HS, Mahajan NP. TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability. Autophagy. 2023 Mar;19(3):1000-1025. doi: 10.1080/15548627.2022.2103961. Epub 2022 Jul 27.

  PMID: 35895804 RESULT

• Sridaran D, Chouhan S, Mahajan K, Renganathan A, Weimholt C, Bhagwat S, Reimers M, Kim EH, Thakur MK, Saeed MA, Pachynski RK, Seeliger MA, Miller WT, Feng FY, Mahajan NP. Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance. Nat Commun. 2022 Nov 14;13(1):6929. doi: 10.1038/s41467-022-34724-5.

  PMID: 36376335 RESULT

• Mahajan NP, Coppola D, Kim J, Lawrence HR, Lawrence NJ, Mahajan K. Blockade of ACK1/TNK2 To Squelch the Survival of Prostate Cancer Stem-like Cells. Sci Rep. 2018 Jan 31;8(1):1954. doi: 10.1038/s41598-018-20172-z.

  PMID: 29386546 RESULT

• Mahajan K, Malla P, Lawrence HR, Chen Z, Kumar-Sinha C, Malik R, Shukla S, Kim J, Coppola D, Lawrence NJ, Mahajan NP. ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer. Cancer Cell. 2017 Jun 12;31(6):790-803.e8. doi: 10.1016/j.ccell.2017.05.003.

  PMID: 28609657 RESULT

MeSH Terms

Conditions

Prostatic Neoplasms

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Study Officials

• Douglas McNeel, MD, PhD

  University of Wisconsin, Madison

  STUDY DIRECTOR

Central Study Contacts

Nupam Mahajan, PhD

CONTACT

8135074903; nupam@technogenesys.com

Gerald Andriole, MD

CONTACT

jerry@technogenesys.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 18, 2024
• First Posted: November 26, 2024
• Study Start: March 13, 2026
• Primary Completion (Estimated): December 30, 2027
• Study Completion (Estimated): March 30, 2028
• Last Updated: March 20, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)