| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Histologically or cytologically confirmed adenocarcinoma of the prostate |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with metastatic castration-resistant prostate cancer |
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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 | 20.0 |
| 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 | 100000004864 |
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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 |
1) To determine the maximum tolerated dose (MTD) and schedule of SRA737 in combination with niraparib in subjects with mCRPC and to determine a recommended Phase 2 dose (RP2D) and schedule of SRA737 in combination with niraparib
2) To assess the preliminary efficacy of SRA737 in combination with niraparib based on overall response rate
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| E.2.2 | Secondary objectives of the trial |
1) To characterize the pharmacokinetic (PK) profiles of SRA737 and niraparib when administered in combination
2) To assess the relationship between response and the presence of selected genomic alterations as detected in tumor tissue and/or circulating tumor deoxyribonucleic acid (ctDNA)
3) To assess additional measures of efficacy of the combination of SRA737 and niraparib
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Dose escalation and expansion cohorts:
1) Written informed consent prior to any trial specific procedures, sampling and analyses.
2) Attained the age of 18 years at the time consent is given.
3) Histologically or cytologically confirmed adenocarcinoma of the prostate.
4) Surgically or medically castrated, with serum testosterone levels of ≤ 50 ng/dL (1.73 nM). For subjects currently being treated with luteinizing hormone-releasing hormone (LHRH) agonists and antagonists, therapy must be continued throughout the trial.
5) Prior treatment with at least 1 prior taxane containing regimen.
6) Prior treatment with at least 1 of the following: abiraterone acetate, enzalutamide, or investigational androgen receptor (AR)-targeted agent. A wash-out period of 4 weeks is required for subjects who received first and second generation anti-androgen therapy including enzalutamide and apalutamide.
7) Disease progression on or after most recent prior therapy for mCRPC; with disease progression in this context being based on any one of the following:
a. PSA progression as defined in Section 6.2.2 with a minimum of 2 consecutive rising levels taken 1 or more weeks apart (per PCWG3 criteria). Minimum starting value should be ≥ 2 ng/mL. If confirmed rise is the only indication of progression, then the minimum starting value should be 1 ng/mL.
b. Radiographic progression of soft tissue by RECIST 1.1 or bone disease by PCWG3 criteria as defined in Appendix G in subjects with:
I. Soft tissue disease, measurable by RECIST 1.1 defined as having 1 or more of the following:
i. Nodal disease (pelvic or extrapelvic [retroperitoneal, mediastinal, thoracic, other]) with lesions ≥ 1.5 cm in the short axis.
ii. Visceral disease (lung, liver, adrenal) with lesions ≥ 1 cm in the long axis.
II. Bone disease (non-measurable) defined as having 2 or more new bone lesions in the absence of measurable soft tissue disease.
8) Life expectancy of at least 12 weeks.
9) Hematological and biochemical indices within the ranges shown below, measured within 1 week prior to the subject receiving their first dose of IMP (as listed in protocol table in the inclusion criteria).
10) World Health Organization (WHO) performance status 0-1 with no deterioration over the 2 weeks prior to trial entry.
11) Evaluable disease as demonstrated by any one of the following: A) Measurable disease per RECIST v1.1; B) Increasing PSA; or C) CTC count of ≥ 5 cells/7.5 mL of blood.
Dose expansion cohort only:
12) At least 20 of the planned 31 subjects must have radiographically measurable disease per RECIST v1.1. The remaining subjects may be eligible by increasing PSA or CTC count of ≥ 5 cells/7.5 mL of blood.
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| E.4 | Principal exclusion criteria |
1) Any prior treatment with a Chk1 inhibitor, or prior treatment with an ATR inhibitor within 6 months prior to receiving the first dose of IMP.
2) Have received the following prior or current anticancer therapy:
a. Radiotherapy within 15 days prior to the first dose of IMP (except for symptom control and where the lesions will not be used as measurable disease)
b. Endocrine therapy within 3 weeks prior to the first dose of IMP (except for LHRH agonists and antagonists for prostate cancer)
c. Chemotherapy within 3 weeks prior to the first dose of IMP
d. Immunotherapy within 6 weeks prior to the first dose of IMP
e. Nitrosoureas or Mitomycin C within 6 weeks prior to the first dose of IMP
f. Other IMPs within 4 weeks prior to the first dose of IMP
3) Untreated brain or meningeal metastases that have not been stable (ie, asymptomatic and not progressing) for at least 8 weeks.
4) Symptomatic or impending spinal cord compression unless appropriately treated and clinically stable.
5) Initiated bisphosphonate or denosumab therapy or adjusted bisphosphonate or denosumab dose/regimen within 4 weeks prior to the first dose of IMP. Subjects on stable bisphosphonate or denosumab regimen are eligible and may continue treatment.
6) Other malignancy within the past 2 years with the exception of adequately treated tumors that are associated with an expected 5-year disease-free survival of approximately 95% or better.
7) Received a platelet transfusion or hematopoietic growth factors within 30 days prior to trial entry.
8) Known history or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML).
9) Ongoing toxic manifestations of previous treatments greater than NCI-CTCAE Grade 1. Exceptions to this are alopecia or certain toxicities, which in the opinion of the investigator and the sponsor or sponsor’s designee monitor should not exclude the subject.
10) Subjects with partners of childbearing potential unless they agree to take measures not to father children by using a highly effective method of contraception. Subjects with pregnant or lactating partners must be advised to use a barrier method of contraception to prevent exposure of the fetus or neonate. Refer to for details.
11) Major surgery from which the subject has not yet recovered.
12) At high medical risk because of nonmalignant systemic disease including active uncontrolled infection.
13) Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
14) Serious cardiac condition, such as concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA] refer to Appendix B), left ventricular ejection fraction < 45% at baseline, history of cardiac ischemia within the past 6 months, or prior history of significant cardiac arrhythmia requiring treatment unless approved by the sponsor.
15) Prior bone marrow transplant or extensive radiotherapy to greater than 25% of bone marrow within 8 weeks.
16) Peanut allergy unless this restriction is removed by the sponsor (refer to Section 5.1 for details).
17) QTcF > 450 msec.
18) Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of IMP (eg, ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
19) Not able to swallow capsules without chewing or crushing. Pre-existing duodenal stent and/or any GI disorder or defect that would, in the opinion of the investigator, interfere with the absorption of IMP.
20)Known allergies, hypersensitivity, or intolerance to niraparib or its excipients, or SRA737’s excipients (refer to Investigator's Brochure).
21. Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
22. Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this trial. Participation in an observational trial or interventional clinical trial which does not involve administration of an IMP and which would not place an unacceptable burden on the subject in the opinion of the investigator and sponsor or sponsor’s designee would be acceptable.
23. Any other condition which in the investigator’s or sponsor’s opinion would not make the subject a good candidate for the clinical trial.
Dose expansion cohort only
24. Known to be positive for mutation of genes hypothesized to confer sensitivity to PARP inhibition (ie, BRCA1, BRCA2, ATM, CHEK2, FANCA, PALB2, BRIP1, and HDAC2) by central laboratory testing. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1) The frequency and severity of treatment emergent SAEs, discontinuations due to AEs, and laboratory abnormalities
2) Response rate: defined as 1 of the following by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria:
A. Objective response rate of soft tissue (visceral or nodal disease) as defined by modified RECIST 1.1 with no evidence of bone progression
B. PSA decline of ≥50% confirmed by a repeat reading at least 4 weeks later
C. Conversion of CTC count from ≥ 5 cells/7.5 mL blood at baseline to < 5 cells/7.5 mL blood nadir confirmed by at least 2 readings 4 weeks apart
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) SAE collection and monitoring will commence at the time the subject gives their written consent to participate in the trial, while AE collection and monitoring will commence at the time the subject receives their first dose of an IMP. The collection and monitoring of SAEs and AEs will continue until 30 days after the last administration of IMP(s). Monthly follow up is required for all SAEs and for those AEs considered drug related.
2) At the end of the trial. |
|
| E.5.2 | Secondary end point(s) |
1) Plasma concentration-time profile and PK parameters including, but not limited to: AUC0-inf (for SRA737 only), AUC0-tau (for SRA737 only), AUC0-24, Cmin (for SRA737 only), Cmax, Ctrough, Tmax, and t½
2) Association of clinical response and presence of genomic markers at baseline
3a) PSA response ≥ 50% based on PCWG3 criteria
3b) PSA response ≥ 90% based on PCWG3 criteria
3c) CTC response defined as CTC count = 0 in 7.5 mL of blood at 8 weeks post baseline
3d) CTC0 response, defined as nadir decline to CTC count = 0 in 7.5 mL blood, confirmed by at least 2 readings 4 weeks apart
3e) Duration of radiologic response based on PCWG3-modified RECIST 1.1
3f) Duration of PSA response
3g) Duration of CTC responses and conversion
3h) Disease control rate based on PCWG3-modified RECIST 1.1
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) 48-hours intensive PK sampling after the initial dose of SRA737 during Day -7 to Day -2; 24-hours intensive PK sampling on Day 1 of Cycles 1 and 2. Predose sampling on Day 1 of C3, 4, 5, and 8. A PK sample collection as soon as feasible after the onset of a DLT.
2) At the end of the trial.
3) At the end of the trial. |
|
| 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 | No |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| The ‘end of trial’ is defined as the date when the last subject has completed the Safety Follow-up visit or the long-term follow-up visit (whichever is later). |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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