| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castration-Resistant Prostate Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Prostate cancer that has spread beyond the prostate and that keeps growing despite of castration |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1: To determine the RP2D of abemaciclib that may be safely administered to patients with mCRPC in combination with abiaterone acetate and prednisone.
Part 1, 2 & 3: To compare the rPFS of patients receiving abiraterone acetate plus prednisone with or without abemaciclib.
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| E.2.2 | Secondary objectives of the trial |
To characterize further the safety profile of the combination of abemaciclib and abiraterone acetate plus prednisone.
To compare the efficacy in patients receiving abiraterone acetate plus prednisone with or without abemaciclib.
Time to Symptomatic Progression.
To characterize the PK of abemaciclib and abiraterone acetate when administered in combination.
To assess patient reported pain
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] Male patients, 18 years of age or greater; willing and able to provide written informed consent.
[2] Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell histology.
[3] Metastatic prostate cancer documented by positive bone scan and/or measurable soft tissue metastatic lesions by computed tomography (CT) or magnetic resonance imaging (MRI). If lymph node metastasis is the only evidence of metastasis, it must be ≥1.5cm in the short axis. Visceral metastasis, including to liver, is allowed.
[4] Serum testosterone level ≤ 1.73 nmol/L (50 ng/dL) at the Screening visit. Patients who have not undergone orchiectomy are required to continue androgen-deprivation therapy (LHRH agonists/antagonists) throughout the study.
[5] Progressive disease at study entry demonstrated during continuous androgen deprivation therapy (ADT)/post orchiectomy defined as one or more of the following criteria:
•Sequence of at least 2 rising PSA values at a minimum of 1-week intervals with the last result being at least 1.0 ng/ml if confirmed rise is the only indication of progression. Patients who received an anti-androgen must have PSA progression after withdrawal (≥ 4 weeks since last flutamide or ≥ 6 weeks since last bicalutamide or nilutamide).
•Radiographic progression per RECIST1.1 for soft tissue and/or per PCWG3 for bone, (i.e., appearance of ≥2 new bone lesions), with or without PSA progression.
[6] Patient must have discontinued all previous treatments for cancer (except androgen-deprivation therapy and bone loss prevention treatment), must have recovered from of all acute toxic effects of prior therapy or surgical procedure to Grade ≤ 1 or baseline (as per Common Terminology Criteria for Adverse Events 4.0) prior to randomization, with the exception of alopecia or peripheral neuropathy AND have a washout period from last dose of prior systemic or radiation therapy.
[7] Able and willing to undergo tumor biopsy of at least one metastatic site (mandatory for part 1 and 2, optional for part 3), which should be collected following determination of eligibility and before initiating study treatment.
[8] Have adequate organ function.
[9] Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
[10] Willing to comply with study procedures, able to swallow large capsules. Patients with reproductive potential must agree to use effective contraception and to not donate sperm during the study and for at least 3 months following the last dose of study treatment.
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| E.4 | Principal exclusion criteria |
[11] Prior therapy with CYP17 inhibitors (including abiraterone acetate, TAK-700, TOK-001 and ketoconazole)
[12] Prior treatment with abemaciclib or any CDK4 & 6 inhibitors
[13] Known or suspected contraindications or hypersensitivity to abiraterone acetate, prednisone or abemaciclib or to any of the excipients.
[14] Prior cytotoxic chemotherapy for metastatic castration resistant prostate cancer (patients treated with docetaxel in the mHSPC are eligible). Prior radiopharmaceuticals for prostate cancer, or prior enzalutamide, apalutamide, sipuleucel-T. Patients who had prior radiation or surgery to all target lesions.
[15] Are currently enrolled in a clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study. Have participated in clinical trial for which treatment assignment is still blinded. If patient has participated in a clinical study involving an investigational product, 3 months or 5 half-lives (whichever is shorter) should have passed. If a patient is currently enrolled in a clinical trial involving non-approved use of a device, then agreement with the investigator and Lilly Clinical Research Physician/Clinical Research Scientist (CRP/CRS) is required to establish eligibility.
[16] Gastrointestinal disorder affecting absorption or inability to swallow large pills.
[17] Have prior malignancies or active concurrent malignancy (with the exception of non-melanomatous skin cancer). Patients with carcinoma in situ of any origin and patients with prior malignancies who are in remission and whose likelihood of recurrence is very low per investigator's judgement are eligible for this study. The Lilly CRP will approve enrollment of patients with prior malignancies in remission before these patients are enrolled.
[18] The patient has serious preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
[19] The patient has an history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. Atrial Fibrillation, or other cardiac arrhythmia requiring medical therapy.
[20] Clinically significant heart disease as evidenced by myocardial infarction, arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart failure or cardiac ejection fraction measurement of < 50% at baseline.
[21] Patients with clinically active or chronic liver disease, moderate/severe hepatic impairment (Child-Pugh Class B and C), ascites or bleeding disorders secondary to hepatic dysfunction.
[22] History of adrenal dysfunction
[23] The patient has active bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening is not required for enrollment
[24] Known or suspected CNS metastatic disease (Baseline screening for CNS metastases is not required unless presence of signs and/or symptoms of involvement).
[25] Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg). Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
[26] Life expectancy < 6 months
[27] Patient treated with drugs known to be strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication at least five half-lives prior to starting study drug.
[28] Have received recent (within 4 weeks prior to randomization) live vaccination. Seasonal flu vaccines that do not contain a live virus are permitted.
[29] Untreated spinal cord compression or evidence of spinal metastases with risk of spinal compression. Structurally unstable bone lesions suggesting impending fracture.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1: Safety (including but not limited to): TEAEs, SAEs, deaths, and clinical laboratory abnormalities
Part 1, 2 & 3: rPFS |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety evaluations will occur at each study visit.
Radiologic assessment every 8 weeks for the first 24 weeks, every 12 weeks thereafter, and within 14 days of symptomatic progression if no radiographic progression yet.
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| E.5.2 | Secondary end point(s) |
The safety endpoints evaluated will include but are not limited to the following: AEs, TEAEs, SAEs, clinical laboratory tests, ECGs, vital signs, and physical examinations.
• ORR and DoR
• OS
• Time to PSA progression
• (If Part 3 is opened) rPFS by blinded, independent, central review (BICR)
Time from randomization to any of the following (whichever occurs earlier):
- Symptomatic Skeletal Event (SSE)
- Pain progression or worsening of disease-related symptoms requiring initiation of a new systemic anti-cancer therapy
- Development of clinically significant symptoms due to loco-regional tumor progression requiring surgical intervention or radiation therapy
Abemaciclib and abiraterone acetate steady state plasma concentrations.
Time to worst pain progression, using the Worst Pain NRS score and the WHO-AL.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety evaluations will occur at each study visit.
Radiologic assessment every 8 weeks for the first 24 weeks, every 12 weeks thereafter, and within 14 days of symptomatic progression if no radiographic progression yet.
Worst pain NRS assessment will occur at baseline, on Day 1 of every cycle (every 4 weeks) and at every visit during post-treatment short-term follow up phase.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Korea, Republic of |
| United States |
| Denmark |
| Germany |
| Netherlands |
| Romania |
| Spain |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| LPLV: date of the last visit or last scheduled procedure for the last patient |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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