Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

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Prostatic Neoplasms

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Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Kennedy Disease

All Drugs and Chemicals

Androgens

Androgen Receptor Antagonists

Androgen Antagonists

Hormones

Hormone Antagonists

40 mg of single-agent TRC253 to be administered as oral capsules once daily

80 mg of single-agent TRC253 to be administered as oral capsules once daily

160 mg of single-agent TRC253 to be administered as oral capsules once daily

240 mg of single-agent TRC253 to be administered as oral capsules once daily

280 mg of single-agent TRC253 to be administered as oral capsules once daily

320 mg of single-agent TRC253 to be administered as oral capsules once daily

TRC253 is a high-affinity, small molecule antagonist of the androgen receptor (AR) with inhibitory activity against wild type AR and specific mutated variants of AR. TRC253 blocks AR nuclear translocation as well as AR binding to DNA and is an antagonist of transcription for wild type AR and mutated AR. TRC253 is orally active and does not have agonist activity towards either the wild type or mutated ARs. TRC253 treatment in the Hershberger assay results in complete inhibition of androgen sensitive organ development. TRC253 is efficacious in an LNCaP xenograft model driven by F876L (also known as F877L) mutant AR.

TRC253

James Freddo, MD

This is a multi-center, first-in-human, open-label, Phase 1/2A dose-escalation study in which eligible patients with metastatic castration-resistant prostate carcinoma (mCRPC) will receive oral doses of TRC253. The study will be conducted in 2 parts: part 1 (dose escalation) and part 2 (dose expansion).

The patient population consists of men ≥18 years of age with adenocarcinoma of the prostate with metastatic disease. Patients who have not undergone orchiectomy must have serum testosterone levels \<50 ng/dL determined within 4 weeks prior to start of study drug, and, if applicable, must have discontinued treatment with first or second generation anti-androgens as specified in the inclusion criteria.

During Part 1 of the study, patients will be assigned sequentially to increasing TRC253 doses. The starting dose of TRC253 is 40 mg once daily, orally. TRC253 doses will be escalated in subsequent cohorts after all patients enrolled in a given cohort have completed the 28-day dose-limiting toxicity (DLT) evaluation period. Dose escalation in Part 1 will follow single-patient dose escalation design until drug-related toxicity occurs. When an initial drug-related toxicity occurs or DLT in a single patient the cohort will be expanded according to 3+3 design rules. Subsequent dose levels will enroll patients based on 3+3 design. At the maximum tolerated dose (MTD) or minimum efficacious dose (MED), up to twelve patients may be enrolled.

Part 2 will consist of two cohorts of initially up to 30 patients (Cohort 1) and up to 30 patients (Cohort 2) to receive TRC253 at the recommended Phase 2 dose (RP2D). The objective of Part 2 is to gather additional information on the safety, pharmacokinetics (PK) and pharmacodynamic (PD) characteristics, and the clinical efficacy of TRC253 in a pre-defined population of patients with metastatic castrate-resistant prostate cancer (mCRPC). Patients enrolled into Part 2 will have received prior treatment with enzalutamide or apalutamide and showed characteristics of acquired resistance based on changes in PSA serum levels. Patients will be centrally screened for the presence of the AR F876L (androgen receptor F876L) mutation from a plasma sample and enrolled into Cohort 1 (AR F876L positive) or Cohort 2 (AR F876L negative). Cohort 2 may be expanded if a specific molecular mechanism sensitizing the mCRPC to TRC253 therapy can be identified retrospectively. Additional patients may be prospectively selected for this specific molecular resistance mechanism and added to Cohort 2 upon recommendation by the medical monitor and Principal Investigators.

Phase 1/2A Study of TRC253, an Androgen Receptor Antagonist, in Metastatic Castration-resistant Prostate Cancer Patients

An Open-label Phase 1/2A Study To Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of TRC253, an Androgen Receptor Antagonist, in Patients With Metastatic Castration-resistant Prostate Cancer

The trial began with single patient dose escalation rules. If 1 of 1 patients at a given dose experienced a DLT, the study transitioned to a 3+3 design. If 1 of 3 patients experienced a DLT, the dose level was expanded to 6 patients. The maximum tolerated dose (MTD) would have been exceeded if ≥ 33% of patients experience DLT at a given dose level. DLT occurred when a patient had 1 or more toxicities outlined in the protocol that was considered at least possibly related to TRC253 during the first 5 weeks of study participation in the trial. In addition, any dose level could be expanded to further explore PK (the target PK concentration associated with activity in preclinical models was 335 ng/mL). The number of DLTs by dose cohort have been presented.

Serum prostate-specific antigen (PSA) response according to Prostate Cancer Working Group (PCWG3) criteria is defined as at least a 50% decrease in PSA from baseline confirmed at least 4 weeks later

Maximum change in QTcF from baseline by dose level

To confirm the recommended phase 2 dose (RP2D), patients at select dose levels will undergo positron emission tomography scan (PET) scans using fluoro-5alpha-dihydrotestosterone (FDHT), a radiopharmaceutical specifically designed to image binding to androgen receptor (AR). Imaging occurred at one center under their existing investigational new drug application (IND) and institutional protocol. A negative change from baseline in the standard uptake value indicate a decrease in metabolic activity of the tumor and indicate increased receptor occupancy of TRC253.

Preliminary anti-tumor effects of TRC253 as assessed by median time to progression by Prostate Cancer Working Group 3 (PCWG3) criteria by dose level

Determine the number of patients who achieved the target concentration of TRC253 at steady state (target efficacy concentration of 335 ng/mL based on preclinical models).

Janssen Pharmaceutica N.V., Belgium

Tracon Pharmaceuticals Inc.

Single-agent TRC253 to be administered as oral capsules once daily.

40 mg TRC253/Daily

80 mg TRC253/Daily

160 mg TRC253/Daily

240 mg TRC253/Daily

280 mg TRC253/Daily

320 mg TRC253/Daily

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race/Ethnicity

Race/Ethnicity, Customized

United States

Region of Enrollment

Charles Theuer, MD PhD

Determination of the maximum tolerated dose.

One dose limiting toxicity occurred at 320 mg daily of grade 3 QTc prolongation therefore the 280 mg dose was determined to be the maximum tolerated dose and selected as the phase 2 dose.

All patients who received at least a portion of a dose of TRC253 are included in the analysis.

Number of Patients Who Experience Dose Limiting Toxicities by Dose Level

Patients with a baseline PSA and at least 1 on study PSA that were confirmed at least 4 weeks later.

Number of Participants With a Serum Prostate-specific Antigen (PSA) Response According to Prostate Cancer Working Group (PCWG3) Criteria

Patients who received at least a portion of a dose of TRC253 with a baseline ECG and at least 1 on study ECG.

Maximum Change in QTcF

TRC253 4 week FDHT-PET response mean SUV based on the 5 hottest lesions (uncorrected)

Percent Change From Baseline in Standard Uptake Value (SUV) to Assess TRC253 Receptor Occupancy

40 mg TRC253/Daily Dose Levels Combined

80 mg TRC253/Daily Dose Levels Combined

160 mg TRC253/Daily Dose Levels Combined

In order to be eligible for efficacy analysis patients must have had a baseline CT scan and at least 1 on study CT scan.

Median Time to Progression by Dose Level

Patients who received at least 75% of planned continuous daily dosing after 28 days of daily dosing enrolled in part 1 of the study.

Number of Patients Who Achieved the Target Concentration of TRC253 at Steady State

Overall Study

Symptoms and General Pathology

Flushing

Hot Flashes

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Antineoplastic Agents

Reproductive Control Agents

Psychotropic Drugs

Vasoconstrictor Agents

Leuprolide

Venlafaxine Hydrochloride

Medroxyprogesterone Acetate

Medroxyprogesterone

Flutamide

Cyproterone Acetate

Cyproterone

Norepinephrine

Serotonin

Serotonin and Noradrenaline Reuptake Inhibitors

Neurotransmitter Agents

Antidepressive Agents

Contraceptive Agents

Contraceptives, Oral

Contraceptives, Oral, Hormonal

Contraceptive Agents, Female

Contraceptive Agents, Hormonal

Contraceptive Agents, Male

Antineoplastic Agents, Hormonal

Leuprorelin 11.25 mg, injection, subcutaneously at Months 0, 3, and 6, and flutamide 250 mg, tablet, orally, thrice daily for first 30 days from first leuprorelin administration. From Month 6, cyproterone acetate 50 mg, tablet-in-capsule, along with cyproterone acetate placebo-matching capsule, orally, once daily in the morning and cyproterone acetate 50 mg, tablet-in-capsule, orally, once daily in the evening for 8 weeks. Cyproterone acetate placebo-matching capsule, orally, once daily in the morning for the next 2 weeks.

Leuprorelin 11.25 mg, injection, subcutaneously at Months 0, 3, and 6, and flutamide 250 mg, tablet, orally, thrice daily for first 30 days from first leuprorelin administration. From Month 6, medroxyprogesterone acetate 10 mg, tablet-in-capsule, along with medroxyprogesterone acetate placebo-matching capsule, orally, once daily in the morning and medroxyprogesterone acetate 10 mg, tablet-in-capsule, orally, once daily in the evening for 8 weeks. Medroxyprogesterone acetate placebo-matching capsule, orally, once daily in the morning for the next 2 weeks.

Leuprorelin 11.25 mg, injection, subcutaneously at Months 0, 3, and 6, and flutamide 250 mg, tablet, orally, thrice daily for first 30 days from first leuprorelin administration. From Month 6, venlafaxine 75 mg, capsule, orally, once daily in the morning and venlafaxine placebo-matching capsule, orally, once daily in the evening for 8 weeks. Venlafaxine 37.5 mg, capsule, orally, once daily in the evening for the next 2 weeks.

Cyproterone acetate

Medroxyprogesterone acetate tablet-in-capsule.

Medroxyprogesterone acetate

Venlafaxine

Leuprorelin

Cyproterone acetate, medroxyprogesterone acetate or venlafaxine placebo-matching capsule.

Placebo

jacques irani, MD

The purpose of this study is to compare the efficacy of three drugs (cyproterone acetate, medroxyprogesterone acetate and venlafaxine) in the treatment of hot flushes caused by leuprorelin LP 11.25 milligram (mg) in participants suffering from prostate cancer.

Three drugs will be tested in this study: cyproterone acetate, medroxyprogesterone acetate and venlafaxine. Cyproterone acetate, medroxyprogesterone acetate and venlafaxine are being tested to treat men who suffer from hot flushes due to androgen suppression treatment for prostate cancer. This study will look at the frequency and severity of hot flushes caused by leuprorelin in participants who will take cyproterone acetate, medroxyprogesterone acetate or venlafaxine. The study will randomize approximately 311 participants. All participants will receive 2 injections of leuprorelin 11.35 mg at Months 0 and 3 along with flutamide tablets in the first month of treatment to prevent flare-up. After 6 months, eligible participants will receive third injection of leuprorelin and will be randomly assigned to one of the three treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* Cyproterone acetate (Androcur® 50 mg)
* Medroxyprogesterone acetate (Gestoral® 10 mg)
* Venlafaxine (Effexor® LP 37.5 mg) All participants will be asked to take 2 capsules in the morning and 1 capsule in the evening for 10 weeks. All participants will be asked to complete the self-evaluation hot-flushes (HF) questionnaire daily for 12 weeks from the start of treatment for hot flushes.

This multi-center trial will be conducted in France. The overall time to participate in this study is approximately 9 months. Participants will make 5 visits to the clinic during the study.

Treatment of Hot Flushes Caused by Leuprorelin 11.25 mg in Prostate Adenocarcinoma

Efficacy and Tolerance of Cyproterone Acetate Versus Medroxyprogesterone Acetate Versus Venlafaxine LP in the Treatment of Hot Flushes Caused by Leuprorelin 11.25 mg in Patients Treated for a Prostate Adenocarcinoma

The change is calculated as follows: \[(HF score at Week 4 of treatment - HF score at randomization)/HF score at randomization\]\*100. The calculation of the HF score will be done as follows: a coefficient is allocated to each severity grade, it varies from 1 to 4 (1: slight; 2: moderate; 3: severe; 4: very severe), and the calculation of the daily score is equal to the sum of the daily instances of hot flushes multiplied by their severity coefficient. The score calculated at randomization and Week 4 of treatment will be the average of the scores recorded in the preceding week. The score range will depend upon the frequency of hot flushes, and higher score signifies higher severity of hot flushes.

The change is calculated as follows: \[(HF frequency at specified Week of treatment - HF frequency at randomization)/HF score at randomization\]\*100.

The percentage of participants with at least 50 % improvement in HF score after 4 weeks of treatment compared to randomization will be calculated. The calculation of the HF score will be done as follows: a coefficient is allocated to each severity grade, it varies from 1 to 4 (1: slight; 2: moderate; 3: severe; 4: very severe), and the calculation of the daily score is equal to the sum of the daily instances of hot flushes multiplied by their severity coefficient. The score range will depend upon the frequency of hot flushes, and higher score signifies higher severity of hot flushes. The score calculated at randomization and Week 4 of treatment will be the average of the scores recorded in the preceding week.

Complete regression at Week 4 of treatment signifies complete disappearance of hot flushes upon 4 weeks of treatment.

Decrease (improvement) in the level of complaint regarding hot flushes will be assessed compared to randomization. Participants' level of complaints about hot flushes was recorded at each visit of the study. The change in the level of complaints will be classified as degradation, non-change or improvement.

The change is calculated as follows: \[(HF score at specified Week of treatment - HF score at randomization)/HF score at randomization\]\*100. The calculation of the HF score will be done as follows: a coefficient is allocated to each severity grade, it varies from 1 to 4 (1: slight; 2: moderate; 3: severe; 4: very severe), and the calculation of the daily score is equal to the sum of the daily instances of hot flushes multiplied by their severity coefficient. The score range will depend upon the frequency of hot flushes, and higher score signifies higher severity of hot flushes. The score calculated at randomization and Week 8 of treatment will be the average of the scores recorded in the preceding week.

The change is calculated as follows: \[(HF score at Week 8 of treatment - HF score at Week 4 of treatment)/HF score at Week 4 of treatment\]\*100. The calculation of the HF score will be done as follows: a coefficient is allocated to each severity grade, it varies from 1 to 4 (1: slight; 2: moderate; 3: severe; 4: very severe), and the calculation of the daily score is equal to the sum of the daily instances of hot flushes multiplied by their severity coefficient. The score range will depend upon the frequency of hot flushes, and higher score signifies higher severity of hot flushes. The score calculated at Weeks 4 and 8 of treatment will be the average of the scores recorded in the preceding week.

The change is calculated as follows: \[(HF frequency at Week 8 of treatment - HF frequency at Week 4 of treatment)/HF score at Week 4 of treatment\]\*100.

Participants will be asked at Week 8 and 12 visits if they would like to continue the study treatment beyond the protocol-specified 10 weeks of treatment.

Participants will be asked at Week 12 visit if they would like to restart the study treatment which ended after 10 weeks.

EORTC QLQ-C30: includes functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions uses 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions uses 7-point scale (1 'very poor' to 7 'Excellent'). Scores are averaged and transformed to 0-100 scale; for the 5 functional scales and the global quality-of-life scale, a higher score represents a better level of functioning. For the symptom-oriented scales and items, a higher score corresponds to a higher level of symptoms.

Participant's satisfaction is assessed by asking them how they would rate the treatment efficacy as not very effective, moderately effective and very effective at 4, 8 weeks of treatment and 12 weeks after the start of treatment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase 1/2A Study of TRC253, an Androgen Receptor Antagonist, in Metastatic Castration-resistant Prostate Cancer Patients	NCT02987829	Metastatic Cast... Adenocarcinoma,...	TRC253	18 Years - 99 Years	Tracon Pharmaceuticals Inc.
Phase 1/2A Study of TRC253, an Androgen Receptor Antagonist, in Metastatic Castration-resistant Prostate Cancer Patients	NCT02987829	Metastatic Cast... Adenocarcinoma,...	TRC253	18 Years - 99 Years	Tracon Pharmaceuticals Inc.
Treatment of Hot Flushes Caused by Leuprorelin 11.25 mg in Prostate Adenocarcinoma	NCT01011751	Adenocarcinoma,...	Cyproterone ace... Medroxyprogeste... Venlafaxine Leuprorelin Flutamide Placebo	18 Years -	Takeda

Spots Global Cancer Trial Database for adenocarcinoma, prostate