Onvansertib in Combination With Abiraterone and Prednisone in Adult Patients With Metastatic Castration-Resistant Prostate Cancer

Phase 2

Completed

• Conditions: Metastatic Castration-Resistant Prostate Cancer
• Interventions: Drug: Onvansertib; Drug: Abiraterone; Drug: Prednisone

• Registration Number: NCT03414034
• Lead Sponsor: Cardiff Oncology

Brief Summary

The purpose of the phase 2 study is to determine whether Onvansertib is safe and tolerable in adult participants with Metastatic Castration-Resistant Prostate Cancer who have disease progression while receiving abiraterone acetate (abiraterone) and prednisone therapy, and to observe the effects of Onvansertib in combination with abiraterone and prednisone on disease control.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-01-22
• Study First Submitted QC: 2018-01-26
• Study First Posted: 2018-01-29
• Study Start: 2018-08-14
• Primary Completion: 2023-10-16
• Study Completion: 2023-10-16
• Status Verified: 2024-10
• Results First Submitted: 2024-10-15
• Results First Submitted QC: 2024-10-15
• Last Update Submitted: 2024-10-15
• Results First Posted: 2024-11-07
• Last Update Posted: 2024-11-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 72

Inclusion Criteria

1. Males ≥ 18 years of age on the day of consenting to the study.

2. Ability to swallow the study drug as a whole tablet.

3. Histologically confirmed prostate adenocarcinoma without significant small- cell/neuroendocrine or other variant histologies, with rising PSA and/or radiographic progression in the setting of castration-level testosterone (< 50 ng/dL) indicating mCRPC. Participants must have either undergone surgical castration or continue on GnRH agonist/antagonist on the appropriate schedule throughout the study period.

4. Asymptomatic or minimally symptomatic disease.

5. Metastatic disease by bone scan or other nodal or visceral lesions on CT or MRI at any time (past or present).

6. Participant currently receiving abiraterone and prednisone for CRPC.

7. Participant has been on abiraterone for castration-sensitive prostate cancer (CSPC) or castration-resistant prostate cancer (CRPC). Participants who have received abiraterone for CSPC must have had a response to hormonal therapy, as defined by any decline in PSA, radiographic response and/or clinical benefit after starting hormonal therapy.

   Participants who have received abiraterone for CRPC must have responded to abiraterone, defined by any decline in PSA, radiographic response, and/or clinical benefit after starting abiraterone.

8. Two rising PSA values separated by at least 1 week, one showing a rise of at least 0.3 ng/mL and one confirmatory value not showing a decline, while on abiraterone therapy.

9. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

10. Participant has adequate bone marrow and organ function as shown by:

    • Absolute neutrophil count (ANC) ≥ 1.0 x 109/L
    • Platelets ≥ 100 x 10^9/L
    • Hemoglobin (Hgb) ≥ 9.0 g/dL
    • Serum creatinine ≤ 2 x the upper limit of normal (ULN)
    • Total serum bilirubin ≤ 1.5 x ULN (in participants with known Gilbert Syndrome, a total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN (or ≤ 5.0 x ULN if hepatic metastases are present)

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Exclusion Criteria

1. Major surgery within 28 days prior to starting study drug or has not recovered from major side effects of the surgery.

2. Rapidly progressive symptoms of mCRPC.

3. Acute neurological dysfunction as a result of bone metastasis.

4. Previously treated with enzalutamide or experimental therapies directed against androgen receptor (ie, apalutamide).

5. Use of any chemotherapy, investigational agents, immunotherapy, or hormonal therapy other than GnRH agonists within 28 days of the start of treatment on protocol.

   Use of bone targeted agents including bisphosphonates and RANK ligand inhibitors is allowed if on stable dose; Xgeva or Zometa cannot be started within 28 days of initiating study therapy.

6. Systemic corticosteroids except as part of on label treatment prostate cancer regimens. Note: Topical applications (eg, rash), inhaled sprays (eg, obstructive airways diseases), eye drops or local injections (eg, intra-articular) are allowed.

7. Treatment with any of the drugs listed in Section 8.4.5 at the time of study treatment initiation.

8. Has received wide field radiotherapy (including therapeutic radioisotopes such as radium 223) ≤ 28 days or limited field radiation for palliation ≤ 14 days prior to starting study drug or has not recovered from side effects of such therapy.

9. New York Heart Association (NYHA) Class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition, or hypertensive or metabolic condition.

10. Myocardial infarction in the previous 12 weeks (from the start of treatment)

11. QT interval with Fridericia's correction [QTcF] >470 milliseconds. The QTcF should be calculated as the arithmetic mean of the QTcF on triplicate ECGs. In the case of potentially correctible causes of QT prolongation (e.g., medications, hypokalemia), the triplicate ECG may be repeated once during screening and that result may be used to determine eligibility.

12. Planned concomitant use of medications known to prolong the QT/QTc interval

13. Presence of risk factors for torsade de pointes, including family history of Long QT Syndrome or uncorrected hypokalemia.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A: onvansertib + abiraterone and prednisone	Prednisone	On Day 1 of each cycle, onvansertib will be administered orally (PO) once daily (QD) at a dose of 24 mg/m\^2 for 5 days (Day 1 through Day 5) out of a 21-day cycle. Beginning on Day 1 and continuing uninterrupted throughout each cycle, participants will also receive abiraterone and prednisone. This arm was discontinued.
Arm B: onvansertib + abiraterone and prednisone	Prednisone	On Day 1 of each cycle, onvansertib will be administered orally (PO) once daily (QD) at a dose of 24 mg/m\^2 for 5 days (Day 1 through Day 5) out of a 14-day cycle. Beginning on Day 1 and continuing uninterrupted throughout each cycle, participants will also receive abiraterone and prednisone.
Arm C: onvansertib + abiraterone and prednisone	Prednisone	On Day 1 of each cycle, onvansertib will be administered orally (PO) once daily (QD) at a dose of 12 mg/m\^2 for 14 days (Day 1 through Day 14) out of a 21-day cycle. Beginning on Day 1 and continuing uninterrupted throughout each cycle, participants will also receive abiraterone and prednisone.
Arm C: onvansertib + abiraterone and prednisone	Onvansertib	On Day 1 of each cycle, onvansertib will be administered orally (PO) once daily (QD) at a dose of 12 mg/m\^2 for 14 days (Day 1 through Day 14) out of a 21-day cycle. Beginning on Day 1 and continuing uninterrupted throughout each cycle, participants will also receive abiraterone and prednisone.
Arm C: onvansertib + abiraterone and prednisone	Abiraterone	On Day 1 of each cycle, onvansertib will be administered orally (PO) once daily (QD) at a dose of 12 mg/m\^2 for 14 days (Day 1 through Day 14) out of a 21-day cycle. Beginning on Day 1 and continuing uninterrupted throughout each cycle, participants will also receive abiraterone and prednisone.
Arm A: onvansertib + abiraterone and prednisone	Abiraterone	On Day 1 of each cycle, onvansertib will be administered orally (PO) once daily (QD) at a dose of 24 mg/m\^2 for 5 days (Day 1 through Day 5) out of a 21-day cycle. Beginning on Day 1 and continuing uninterrupted throughout each cycle, participants will also receive abiraterone and prednisone. This arm was discontinued.
Arm B: onvansertib + abiraterone and prednisone	Abiraterone	On Day 1 of each cycle, onvansertib will be administered orally (PO) once daily (QD) at a dose of 24 mg/m\^2 for 5 days (Day 1 through Day 5) out of a 14-day cycle. Beginning on Day 1 and continuing uninterrupted throughout each cycle, participants will also receive abiraterone and prednisone.
Arm A: onvansertib + abiraterone and prednisone	Onvansertib	On Day 1 of each cycle, onvansertib will be administered orally (PO) once daily (QD) at a dose of 24 mg/m\^2 for 5 days (Day 1 through Day 5) out of a 21-day cycle. Beginning on Day 1 and continuing uninterrupted throughout each cycle, participants will also receive abiraterone and prednisone. This arm was discontinued.
Arm B: onvansertib + abiraterone and prednisone	Onvansertib	On Day 1 of each cycle, onvansertib will be administered orally (PO) once daily (QD) at a dose of 24 mg/m\^2 for 5 days (Day 1 through Day 5) out of a 14-day cycle. Beginning on Day 1 and continuing uninterrupted throughout each cycle, participants will also receive abiraterone and prednisone.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Achieving Disease Control at or Before 12 Weeks	Baseline up to Week 12	Disease control was defined as lack of prostate-specific antigen (PSA) progression per Prostate Cancer Working Group 3 (PCWG3) criteria: not having an increase in PSA from Baseline or nadir ≥ 25% and ≥ 2 ng/mL during the first 12 weeks of PSA assessments. Participants that do not have 12 weeks of PSA assessments were considered not to have demonstrated PSA progression control in this analysis. If a participant achieved disease control prior to Week 12, but relapsed at, or before Week 12, disease control was still considered achieved. The 90% confidence intervals were calculated using Wilson Confidence Interval.

Secondary Outcome Measures

Name	Time	Method
Mean Percentage Change From Baseline in PSA at 12 Weeks	Baseline and Week 12	PSA level was measured via blood sample. Mean and standard deviation change is reported.
Mean Absolute Change From Baseline in PSA at 12 Weeks	Baseline and Week 12	PSA level was measured via blood sample. Mean and standard deviation change is reported.
Median Percentage Change From Baseline in PSA at 12 Weeks	Baseline and Week 12	PSA level was measured via blood sample. Median, minimum and maximum change is reported.
Median Absolute Change From Baseline in PSA at 12 Weeks	Baseline and Week 12	PSA level was measured via blood sample. Median, minimum and maximum change is reported.
Time to PSA Progression or Death	Up to approximately 100 weeks	Time to PSA progression in weeks is defined as time from Cycle 1 Day 1 (initiation of treatment) until initiation of any PSA progression per PCWG3 criteria: an increase in PSA from Baseline or nadir ≥ 25% and ≥ 2 ng/mL. If a participant discontinued from the study without confirmed PSA progression or death, then they were censored at the last PSA laboratory date. Kaplan-Meier method was used.
Time to Radiographic Progression or Death	Up to approximately 110 weeks	Time to radiographic progression in weeks is defined as time from Cycle 1 Day 1 (initiation of treatment) until initiation of any radiographic progression per PCWG3 criteria. If a participant discontinued from the study without confirmed radiographic progression or death, then they were censored at the last valid assessment date.
Percentage of Participants Achieving Radiographic Responses at or Before 12 Weeks	Baseline up to Week 12	Radiographic response is defined as the best overall response between Cycle 1 Day 1 and 12 weeks post-baseline being stable disease (SD) or better (partial response \[PR\] or complete response \[CR\]) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1): CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis).; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters.; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD).; PD: at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions.
Percentage of Participants Who Are Adherent to Study Treatment (PP Analysis) Achieving Disease Control at or Before 12 Weeks	Baseline up to Week 12	Disease control was defined as lack of PSA progression per PCWG3 criteria: not having an increase in PSA from Baseline or nadir ≥ 25% and ≥ 2 ng/mL during the first 12 weeks of PSA assessments. Participants that do not have 12 weeks of PSA assessments were considered not to have demonstrated PSA progression control in this analysis. If a participant achieved disease control prior to Week 12, but relapsed at, or before Week 12, disease control was still considered achieved. The 90% confidence intervals were calculated using Wilson Confidence Interval.
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	Up to approximately 27 months	Adverse events (AEs) are defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. TEAEs are defined as AEs with a start date after Cycle 1 Day 1. AE severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 on a scale from Grade 1 (mild) to Grade 5 (death related to AE).
Number of Participants With DLTs	Arms A and B: up to one 21-day cycle; Arm C: up to two 14-day cycles	DLTs are defined as a CTCAE Grade 4 hematologic AE or CTCAE Grade ≥ 3 non-hematologic AE that is considered related to the study drug.

Trial Locations

Locations (3)

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center; 🇺🇸 Boston, Massachusetts, United States