ProSTAR: A Study Evaluating CPI-1205 in Patients With Metastatic Castration Resistant Prostate Cancer

PHASE 1b DOSE ESCALATION

Inclusion Criteria for Phase 1b Dose Escalation

Patients must meet all the following criteria to be enrolled in this study:

1. Age ≥ 18 years
2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
3. Life expectancy of at least 12 weeks
4. Histologically or cytologically confirmed adenocarcinoma of the prostate (pure small cell carcinoma excluded)
5. Documented metastatic disease
6. Must have undergone bilateral orchiectomy (surgical castration) or willing to continue gonadotropin-releasing hormone (GnRH) analog or antagonist (medical castration)
7. Serum testosterone \< 50 ng/dL
8. Progressive disease in the setting of medical or surgical castration (i.e., Castration-resistant Prostate Cancer \[CRPC\]) as assessed by the investigator and includes at least one of the following:

   1. Evidence of progression as measured by PSA increase of ≥ 25% and an absolute increase of ≥ 2 ng/mL in \< 6 months from end of last therapy prior to enrollment and/or
   2. Soft tissue disease progression as per Response Evaluation Criteria in Solid Tumors (RECIST) and/or
   3. Bone disease progression defined by two or more new lesions on bone scan
9. Bisphosphonate or denosumab therapy allowed provided dose has been stable for at least 4 weeks prior to Day 1 of treatment
10. Prior treatment:

    1. Prior treatment for metastatic CRPC (mCRPC) must have included at least one line with a second-generation androgen inhibitor (e.g., abiraterone, enzalutamide, apalutamide, daralutamide)
    2. Prior chemotherapy permitted when administered in the metastatic hormone-sensitive prostate cancer setting. In addition, up to one line of chemotherapy is allowed in the mCRPC setting.
    3. Prior treatment with sipuleucel-T, radium-223, or other non-chemotherapy based treatments for mCRPC (e.g., olaparib, pembrolizumab) is allowed.
11. Recovery from recent surgery, radiotherapy, chemotherapy or other anti-cancer treatment to baseline or ≤ Grade 1 (other than alopecia)
12. Demonstrate adequate organ function as defined in the table below; all Screening labs obtained within 28 days prior to Day 1 of treatment.
13. Patients who have not undergone a bilateral orchiectomy and have a female partner of childbearing potential must use an adequate barrier method of contraception during study treatment and for 90 days after receiving the last dose of CPI-1205
14. Willing to provide access to archival tumor tissue for research purposes
15. Ability to swallow and retain oral medications
16. Ability to understand and willingness to sign an IRB approved written informed consent form (ICF) and authorization permitting release of personal health information including genetic testing relevant to cancer.
17. Able to comply with study visit schedule and assessments

Exclusion Criteria for Phase 1b Dose Escalation

Patients who meet any of the following criteria will not be enrolled in the study:

1. Known symptomatic brain metastases
2. Treatment with any of the following for prostate cancer within the indicated timeframe prior to Day 1 of treatment

   1. First generation: AR antagonists (e.g., bicalutamide, nilutamide, flutamide) within 4 weeks
   2. 5 alpha reductase inhibitors, ketoconazole, estrogens (including diethylstilbesterol \[DES\]), or progesterones within 2 weeks
   3. Chemotherapy within 3 weeks
   4. Biologic therapy within 4 weeks
   5. Investigational therapy within 3 weeks (or within a time interval less than at least 5 half-lives of the investigational agent \[if known\], whichever is longer).
   6. Immunotherapy within 4 weeks
   7. Radionuclide therapy within 4 weeks
3. Radiation therapy for the treatment of metastasis within 1 week prior to Day 1 of treatment
4. Herbal products that may decrease PSA levels within 4 weeks prior to day 1 of treatment
5. Systemic steroids greater than 10 mg of prednisone/prednisolone per day within 4 weeks prior to day 1 of treatment
6. Major surgery within 4 weeks prior to Day 1 of treatment
7. Planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery
8. Structurally unstable bone lesions concerning for impending fracture
9. Clinically significant cardiovascular disease including:

   1. Myocardial infarction (MI)/Stroke within 6 months prior to Day 1 of treatment
   2. Uncontrolled angina within 3 months
   3. Congestive heart failure (CHF) with New York Heart Association (NYHA) Class 3 or 4
   4. History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)
   5. Uncontrolled hypertension (systolic blood pressure (BP) \> 170 mmHg or diastolic BP \> 105 mmHg at screening) despite 2 concomitant antihypertensive therapies
   6. QT interval corrected by the Fridericia correction formula (QTcF) \> 500 msec on the screening ECG
10. Active or symptomatic viral hepatitis or chronic liver disease
11. History of unresolved adrenal dysfunction
12. GI disorder that negatively affects absorption
13. Required treatment with one of the prohibited concomitant medications;
14. Achlorhydria, either documented or suspected on the basis of an associated disease (e.g., pernicious anemia, atrophic gastritis, or certain gastric surgical procedures)
15. History of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within 12 months prior to Day 1 of treatment, cerebral vascular accident or brain arteriovenous malformation
16. Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ bladder cancer, or other cancer for which the patient has been disease-free for at least two years
17. Any other concurrent severe and/or uncontrolled concomitant medical condition that could compromise participation in the study (e.g., clinically significant pulmonary disease, clinically significant psychiatric or neurological disorder, active or uncontrolled infection)
18. Patient unwilling or unable to comply with this study protocol

PHASE 1b: HEAVILY PRETREATED EXPANSION COHORT (HPEC)

Inclusion Criteria for Phase 1b HPEC

Patients must meet all the following criteria to be enrolled in this study:

1. Age ≥ 18 years
2. ECOG Performance Status 0-1
3. Life expectancy of at least 12 weeks
4. Histologically or cytologically confirmed adenocarcinoma of the prostate (pure small cell carcinoma excluded)
5. Documented metastatic disease
6. At least 1 measurable lymph node per Prostate Cancer Clinical Trials Working Group 3 (PCWG3)
7. Must have undergone bilateral orchiectomy (surgical castration) or willing to continue GnRH analog or antagonist (medical castration)
8. Serum testosterone \< 50 ng/dL
9. Progressive disease in the setting of medical or surgical castration (i.e., CRPC) as assessed by the investigator and that includes at least 1 of the following:

   1. Evidence of progression as measured by PSA defined as: PSA at least 2 ng/mL (or PSA at least 1 ng/mL if PSA progression is the only manifestation of progressive disease) and rising PSA by at least 2 consecutive measurements a minimum of 1-week apart and/or
   2. Soft tissue disease progression as per RECIST 1.1 and/or
   3. Bone disease progression defined by two or more new lesions on bone scan
10. Prior treatment:

    1. Only 1 prior line of a second-generation androgen inhibitor from a different class than the one chosen for the applicable phase 2 study (the 2 classes are CYP17 inhibitors \[e.g., abiraterone, orteronel\] and AR inhibitors \[e.g., enzalutamide, apalutamide\]). Patient must have progressed after ≥ 24 weeks of treatment with this second generation angrogen inhibitor.
    2. The last second-generation androgen inhibitor treatment received must not be from the same class as that incorporated in the applicable HPEC; i.e., if the HPEC incorporates enzalutamide, the last second generation androgen inhibitor therapy cannot be enzalutamide, apalutamide, etc.
    3. Prior chemotherapy for mCRPC must have included at least 1 and no more than 2 prior lines of taxane-based chemotherapy administered in the metastatic hormone-sensitive prostate cancer setting is allowed
    4. Prior treatment with sipuleucel-T, radium-223, or other non-chemotherapy-based treatments for mCRPC (e.g., olaparib, pembrolizumab, nivolumab) is allowed.
11. Recovery from recent surgery, radiotherapy, chemotherapy or other anti-cancer treatment to baseline or ≤ Grade 1 (other than alopecia)
12. Demonstrate adequate organ function as defined in the table below; all Screening labs to be obtained within 28 days prior to Day 1 of treatment
13. Patients who had not undergone a bilateral orchiectomy and have a female partner of childbearing potential must use an adequate barrier method of contraception during study treatment and for 90 days after receiving the last dose of CPI-1205
14. Willing to provide access to archival tumor tissue for research purposes
15. Ability to swallow and retain oral medications
16. Ability to understand and willingness to sign an IRB approved written ICF and authorization permitting release of personal health information including genetic testing relevant to cancer.
17. Able to comply with study visit schedule and assessments

Exclusion Criteria for Phase 1b HPEC

Patients meeting any of the following criteria will not be enrolled in the study:

1. Known symptomatic brain metastases
2. Treatment with any of the following for prostate cancer within the indicated timeframe prior to Day 1 of treatment

   1. First-generation: AR antagonists (e.g., bicalutamide, nilutamide, flutamide) within 4 weeks
   2. 5-alpha reductase inhibitors, ketoconazole, estrogens (including DES), or progesterones within 2 weeks
   3. Chemotherapy within 3 weeks
   4. Biologic therapy within 4 weeks
   5. Investigational therapy within 3 weeks (or within a time interval less than at least 5 half-lives of the investigational agent \[if known\], whichever is longer).
   6. Immunotherapy within 4 weeks
   7. Radionuclide therapy within 4 weeks
3. Radiation therapy for the treatment of metastasis within 1 week prior to Day 1 of treatment
4. Herbal products that may decrease PSA levels within 4 weeks prior to Day 1 of treatment
5. Systemic steroids greater than 10 mg of prednisone/prednisolone per day within 4 weeks prior to Day 1 of treatment
6. Major surgery within 4 weeks prior to Day 1 of treatment
7. Structurally unstable bone lesions concerning for impending fracture
8. Clinically significant cardiovascular disease including:

   1. MI/Stroke within 6 months prior to Day 1 of treatment
   2. Uncontrolled angina within 3 months
   3. CHF with NYHA Class 3 or 4
   4. History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)
   5. Uncontrolled hypertension (systolic BP \> 170 mmHg or diastolic BP \> 105 mmHg at screening) despite two concomitant antihypertensive therapies
   6. QTcF \>500 msec on the screening ECG
9. Active or symptomatic viral hepatitis or chronic liver disease
10. History of unresolved adrenal dysfunction
11. GI disorder that negatively affects absorption
12. Required treatment with one of the prohibited concomitant medications
13. Achlorhydria, either documented or suspected on the basis of an associated disease (e.g., pernicious anemia, atrophic gastritis, or certain gastric surgical procedures)
14. History of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within 12 months prior to day 1 of treatment, cerebral vascular accident or brain arteriovenous malformation
15. Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ bladder cancer, or other cancer for which the patient has been disease-free for at least 2 years
16. Any other concurrent severe and/or uncontrolled concomitant medical condition that could compromise participation in the study (e.g., clinically significant pulmonary disease, clinically significant psychiatric or neurological disorder, active or uncontrolled infection)
17. Patient unwilling or unable to comply with this study protocol

PHASE 2

Phase 2 Inclusion Criteria

Patients must meet all of the following criteria to be enrolled in this study:

1. Age ≥ 18 years
2. ECOG Performance Status 0-1
3. Life expectancy of at least 12 weeks
4. Histologically or cytologically confirmed adenocarcinoma of the prostate (pure small cell carcinoma excluded)
5. Documented metastatic disease
6. Must have undergone bilateral orchiectomy (surgical castration) or willing to continue GnRH analog or antagonist (medical castration).
7. Serum testosterone \<5 0 ng/dL
8. Progressive disease in the setting of medical or surgical castration (i.e., CRPC) as assessed by the investigator and that includes at least 1 of the following:

   1. Evidence of progression as measured by PSA defined as: PSA greater than or equal to 2 ng/mL (or PSA greater than or equal to 1 ng/mL if PSA progression is the only manifestation of progressive disease) and rising PSA by at least 2 consecutive measurements a minimum of 1-week apart and/or
   2. Soft tissue disease progression as per RECIST 1.1 and/or
   3. Bone disease progression defined by two or more new lesions on bone scan
9. Bisphosphonate or denosumab therapy allowed provided dose has been stable for ≥ 4 weeks prior to Day 1 of treatment.
10. Prior treatment:

    1. Only one prior line of a second-generation androgen inhibitor from a different class than the one chosen for the applicable phase 2 study (the 2 classes are CYP17 inhibitors \[e.g., abiraterone, orteronel\] and AR inhibitors \[e.g., enzalutamide, apalutamide\]). Patient must have progressed after ≥ 24 weeks of treatment with this second generation angrogen inhibitor
    2. No prior chemotherapy for mCRPC allowed; chemotherapy (including taxane-based) administered in the metastatic hormone-sensitive prostate cancer setting is allowed.
    3. Prior treatment with sipuleucel-T, radium-223, or other non-chemotherapy based treatments approved by the US FDA for the treatment of mCRPC is allowed; prior treatment with non-chemotherapy based treatments that are not approved for the treatment of mCRPC (e.g., pembrolizumab, ipilimumab, olaparib) are not allowed.
11. Recovery from recent surgery, radiotherapy, chemotherapy or other anti-cancer treatment to baseline or ≤ Grade 1 (other than alopecia)
12. Demonstrate adequate organ function
13. Patients who have not undergone a bilateral orchiectomy and have a female partner of childbearing potential must use an adequate barrier method of contraception during study treatment and for 90 days after receiving the last dose of CPI-1205 (or partner drug in the control arm of any randomized phase 2 trial if the patient does not participate in the crossover).
14. Willing to provide access to archival tumor tissue for research purposes, if available
15. Ability to swallow and retain oral medications.
16. Ability to understand and willingness to sign an IRB approved written ICF and authorization permitting release of personal health information including genetic testing relevant to cancer.
17. Able to comply with study visit schedule and assessments

Phase 2 Exclusion Criteria

Patients who meet any of the following criteria will not be enrolled in the study:

1. Known symptomatic brain metastases
2. Treatment with any of the following for prostate cancer within the indicated timeframe prior to Day 1 of treatment

   1. First-generation AR antagonists (e.g., bicalutamide, nilutamide, flutamide) within 4 weeks
   2. 5-alpha reductase inhibitors, ketoconazole, estrogens (including DES), or progesterones within 2 weeks
   3. Chemotherapy within 3 weeks
   4. Biologic therapy within 4 weeks
   5. Radionuclide therapy within 4 weeks
3. Radiation therapy for the treatment of metastasis within 1 week prior to Day 1 of treatment
4. Herbal products that may decrease PSA levels within 4 weeks prior to Day 1 of treatment
5. Systemic steroids \> 10 mg of prednisone/prednisolone per day within 4 weeks prior to Day 1 of treatment
6. Major surgery within 4 weeks prior to Day 1 of treatment
7. Planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery
8. Structurally unstable bone lesions concerning for impending fracture
9. Clinically significant cardiovascular disease including:

   1. MI/stroke within 6 months prior to day 1 of treatment
   2. Unstable angina within 3 months
   3. CHF with NYHA Class 3 or 4
   4. History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)
   5. Uncontrolled hypertension (systolic BP \> 170 mmHg or diastolic BP \> 105 mmHg at screening) despite two concomitant antihypertensive therapies
   6. QTcF \> 500 msec on the screening ECG
10. Active or symptomatic viral hepatitis or chronic liver disease
11. History of unresolved adrenal dysfunction
12. GI disorder that negatively affects absorption
13. Required treatment with one of the prohibited concomitant medications
14. Achlorhydria, either documented or suspected on the basis of an associated disease (e.g., pernicious anemia, atrophic gastritis, or certain gastric surgical procedures)
15. History of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within 12 months prior to Day 1 of treatment, cerebral vascular accident or brain arteriovenous malformation
16. Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ bladder cancer, or other cancer for which the patient has been disease-free for at least two years
17. Any other concurrent severe and/or uncontrolled concomitant medical condition that could compromise participation in the study (e.g., clinically significant pulmonary disease, clinically significant psychiatric or neurological disorder, active or uncontrolled infection)
18. Patient unwilling or unable to comply with this study protocol