| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with histologically or cytologically proven advanced solid tumours, refractory to conventional treatment, or for which no conventional therapy is considered appropriate by the Investigator. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with advanced solid tumours. |
|
| 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 | 10007050 |
| E.1.2 | Term | Cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 establish the safety profile of SRA737.
2) To determine the maximum tolerated dose with 1 or more schedules of administrations of SRA737.
3) To propose a recommended Phase 2 dose and schedule of SRA737.
4) To evaluate the preliminary efficacy of SRA737 including efficacy in prospectively-selected genetically-defined subjects enrolled into indication-specific expansion cohorts. |
|
| E.2.2 | Secondary objectives of the trial |
1) To characterize the pharmacokinetic profile of SRA737.
2) To assess the relationship between response and the presence of selected genetic alterations as detected in tumor tissue and/or circulating tumor deoxyribonucleic acid (ctDNA). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Dose Escalation Phase and Cohort Expansion Phase:
1) Written (signed and dated) informed consent and be capable of cooperating with treatment and follow up.
2a) For subjects in the Dose Escalation Phase: any locally advanced or metastatic, histologically or cytologically proven solid tumor or NHL, relapsed after or progressing despite conventional treatment and for which no other conventional therapy is considered appropriate by the investigator or has been declined by the subject.
2b) For subjects in the Cohort Expansion Phase: any locally advanced or metastatic, histologically or cytologically proven malignancy of the types specified in inclusion criterion 10, for which no other conventional therapy is considered appropriate by the investigator or has been declined by the subject.
3) Life expectancy of at least 12 weeks.
4) World Health Organization (WHO) performance status of 0–1.
5) Hematological and biochemical indices within the ranges shown below, measured within one week prior to the subject receiving their first dose of investigational medicinal product (IMP).
Hemoglobin - ≥ 90 g/L
Absolute neutrophil count - ≥ 1.5 x 10^9/L
Platelet count - ≥ 100 x 10^9/L
Bilirubin - ≤ 1.5 x upper limit of normal (ULN) unless due to Gilbert’s syndrome in which case up to 3 × ULN is permissible
Alanine aminotransferase and/or aspartate aminotransferase (and Alkaline Phosphatase) - ≤ 2.5 x ULN unless raised due to tumor in which case up to 5 x ULN is permissible
Serum Creatinine - ≤ 1.5 x ULN
6) Subject has attained the age of 18 years at the time consent is given.
7) Subjects must have archival tumor tissue available for tumor profiling or accessible tumor and willingness to consent to a biopsy for the collection of tumor tissue.
Cohort Expansion Phase:
8) Subjects must have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), or for mCRPC, evaluable disease per a composite of any one of the following: A) Measurable disease per RECIST v1.1; B) Increasing prostate specific antigen (PSA, see Prostate Cancer Clinical trials Working Group [PCWG] Guidelines - Appendix 7); or C) circulating tumor cell (CTC) count of 5 or more cells per 7.5ml of blood.
9) Subjects must have tumor tissue or ctDNA evidence that their tumor harbors a combination of mutations which are expected to confer sensitivity to Chk1 inhibition. Eligibility will be determined by the Sponsor’s review of genetic abnormalities detected in genes in the following categories, as listed in Appendix 6: a) Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as RB1, TP53, etc. For patients with HNSCC or SCCA, positive HPV status is also considered for eligibility.
b) The DNA damage response pathway including ATM, BRCA1, and BRCA2. For patients with CRC, mismatch repair genetic alterations and/or high microsatellite instability are also considered for eligibility. c) Genetic indicators of replicative stress such as gain of function/amplification of Chk1 or ATR or other related gene.
d) Oncogenic drivers such as MYC, KRAS, etc.
e) CCNE1 gene amplification (or alternative genetic alteration with similar functional effect) is required for the CCNE1 gene amplification-specific HGSOC cohort.
10) Subjects must meet one of the following criteria (a-e):
a) Metastatic CRC
• Histologically and/or cytologically confirmed CRC
• Must have received at least 1 prior regimen for advanced/metastatic disease
b) HGSOC
• Histologically confirmed high grade serous ovarian, fallopian tube or primary peritoneal cancer
• Recurrent platinum-intolerant subjects, or those with platinum-resistant disease, defined as radiological evidence of disease progression within 6 months of the last receipt of platinum-based chemotherapy. Patients with platinum refractory disease (as defined by the European Society for Medical oncology [ESMO] Guidelines - Appendix 7) are not eligible.
c) Advanced NSCLC
• Locally advanced and recurrent or metastatic, histologically confirmed NSCLC
• Must have received at least 1 prior regimen for advanced/metastatic disease
d) mCPRC
• Histologically or cytologically confirmed adenocarcinoma of the prostate that has progressed after androgen deprivation therapy,
e) NHSCC or SCCA
• Histologically confirmed HNSCC, from any primary site, or SCCA
• For HNSCC: locally advanced disease (ie, persistent or progressive disease following curative-intent radiation, and not a candidate for surgical salvage due to incurability or morbidity), or metastatic disease
• For SCCA: locally advanced disease or metastatic disease for which no curative intent therapy is available
• Must have received at least 1 prior regimen for advanced/metastatic disease |
|
| E.4 | Principal exclusion criteria |
1) Have received the following prior or current anticancer therapy:
a) Radiotherapy within the last 6 weeks (except for symptom control and where the lesions will not be used as measurable disease)
b) Endocrine therapy during the previous 4 weeks except for luteinizing hormone releasing hormone (LHRH) agonists for prostate cancer
c) Chemotherapy during the previous 4 weeks
d) Immunotherapy during the previous 6 weeks
e) Nitrosoureas or Mitomycin C during the previous 6 weeks
f) Other IMPs during the 4 weeks before treatment
g) Any prior treatment with a Chk1 inhibitor, or prior treatment with an ATR inhibitor within 6 months prior to receiving SRA737.
2) 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.
3) Ongoing toxic manifestations of previous treatments greater than National Cancer Institute – Common Terminology Criteria for Adverse Events (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.
4a) For subjects in the Dose Escalation Phase that are not to be included in the Expansion Cohort, new or progressing brain metastases. Subjects with brain metastases that have been radiologically stable over an 8-week period may be included.
4b) For subjects in the Cohort Expansion Phase, present or prior brain metastases.
5) Women of childbearing potential (WOCBP) or women who are already pregnant or lactating. However, those patients who have a negative serum or urine pregnancy test before enrollment and agree to use two forms of contraception or agree to sexual abstinence, effective from the first administration of SRA737, throughout the trial and for six months afterwards are considered eligible.
6) Male subjects with partners of childbearing potential (unless they agree to take measures not to father children by using a barrier method of contraception from the first administration of SRA737 through the trial and for 6 months after their final SRA737 dose). Men with pregnant or lactating partners must be advised to use barrier method contraception (eg, condom plus spermicidal gel) to prevent exposure of the fetus or neonate.
7) Major surgery from which the subject has not yet recovered.
8) At high medical risk because of nonmalignant systemic disease including active uncontrolled infection.
9) Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
10) Serious cardiac condition, such as concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA]), left ventricular ejection fraction < 45% at baseline, history of cardiac ischemia within the past 6 months, or prior history of cardiac arrhythmia requiring treatment.
11) Prior bone marrow transplant or extensive radiotherapy to greater than 25% of bone marrow within 8 weeks.
12) Peanut allergy.
13) QTcF > 450 msec in adult males and > 470 msec in adult females.
14) Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of SRA737 (eg, ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
15) Not able to swallow capsules without chewing or crushing.
16) Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase 1/2 study of SRA737. 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.
17) Any other condition which in the investigator’s opinion would not make the subject a good candidate for the clinical trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1) Safety parameters (referencing National Cancer Institute – Common Terminology Criteria for Adverse Events [NCI-CTCAE] v4.03) including: incidence, seriousness, severity and causality of each AE to SRA737, timing of AE onset, AE duration, and AEs leading to interruption, modification, or discontinuation of study treatment, and primary reason for discontinuation of study treatment if other than disease progression [PD], laboratory (eg, clinical chemistry, hematology, urinalysis) and vital sign data
2) The highest dose at which ≤ 33% of subjects have a dose limiting toxicity (DLT) in a cohort of up to 6 subjects
3) A safe and well tolerated dose and schedule that provides high exposure, based on all available PK, PDn, and safety parameter data from all cycles of therapy
4) Objective response rate (ORR). Disease control rate (DCR). Time to response (TTR). Duration of response (DOR). Progression-free survival (PFS). Time to progression (TTP). Overall survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) For eligible patients, SAE and AE collection and monitoring commences from the time the patient gives their written consent to participate in the trial and will continue until 30 days after the last administration of SRA737 or until the patient starts another anti-cancer therapy. Monthly follow up of AEs and SAEs considered drug-related with a causality of possible, probable or highly probable will continue until the events resolve, return to baseline, stabilise or the patient starts another anti-cancer therapy.
2) At the end of the dose escalation phase.
3) At the end of the trial.
4) At the end of the trial. |
|
| E.5.2 | Secondary end point(s) |
1) Plasma concentration-time profile based on PK parameters including, but not limited to: AUCinf, AUCtau, Cmax, Cmin, Tmax, and t1/2
2) ORR and gene alterations in tumor tissue or ctDNA at baseline as measured by next generation sequencing (NGS). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Blood samples will be taken at up to 11 timepoints over a 24 - 48 hour period following the PK dose (Day -7 to Day -4) and repeated on either Cycle 1 Day 15 or Cycle 1 Day 22.
2) 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 | Yes |
| 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) | 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 | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| 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 | 15 |
| 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 patient has completed the Safety Follow-up visit or the long-term follow-up visit (whichever is later). |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
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