| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Histologically or cytologically proven solid tumours where treatment with gemcitabine plus cisplatin or gemcitabine alone 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 | 10049280 |
| E.1.2 | Term | Solid tumour |
| 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 administered in combination with gemcitabine +/- cisplatin.
2) To determine the maximum tolerated dose (MTD) of SRA737 administered in combination with gemcitabine
3) To define a recommended Phase 2 dose (RP2D) of SRA737 in combination with gemcitabine
|
|
| E.2.2 | Secondary objectives of the trial |
1) To characterize the pharmacokinetic (PK) profile of SRA737 administered in combination with gemcitabine ± cisplatin
2) To assess clinical activity of SRA737 in combination with gemcitabine. Activity of SRA737 in combination with gemcitabine + cisplatin will also be explored as feasible based on the number of subjects enrolled.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Dose-Escalation and Cohort Expansion:
1) Written, signed, and dated informed consent
2) In the Dose Escalation Phase, subjects with a locally advanced or metastatic, histologically or cytologically proven solid tumor, relapsed
after or progressing despite conventional treatment for which no conventional therapy is considered appropriate by the investigator or is
declined by the subject
3) Life expectancy: at least 12 weeks
4) World Health Organization performance status: 0-1
5) Hematological and biochemical indices within the ranges shown below, measured within 1 week prior to the subject receiving their first
dose of SAR737 (or gemcitabine if the SRA737 dose for PK is omitted)
Hemoglobin - ≥ 90 g/L
Absolute neutrophil count - ≥ 1.5 × 10^9/L
Platelet count - ≥ 100 × 10^9/L
Bilirubin - ≤ 1.5 × upper limit of normal (ULN) unless due to Gilbert's syndrome in which case up to 3 × ULN is permissible
Alanine aminotransferase and aspartate aminotransferase and Alkaline Phosphatase - ≤ 2.5 × ULN unless raised due to tumor in which case up
to 5 × ULN is permissible
Serum Creatinine - ≤ 1.5 × ULN
Electrolytes: magnesium, potassium and calcium - If electrolyte levels are low, it must be demonstrated that they can be normalized and
maintained using supplements prior to the subject beginning study treatment. Supplement use should continue while on study as
appropriate
6) Subjects who are 18 years or older
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:
8) Subjects in the indication specific cohort expansion must have histologically or cytologically proven advanced malignancy of the types
specified in Inclusion Criterion 11
9) Have measurable disease according to Response Evaluation Criteria in Solid Tumors, Version 1.1
10) Subjects must have predicted sensitivity to Chk1 inhibition
a. For subjects with HGSOC, documented somatic or germline BRCA1 and BRCA2 wild-type status will confer eligibility without requirement for
prospective genetic profiling. If documented BRCA status is not available, genetic profiling may be performed prospectively to determine
eligibility
b. Subjects with SCLC are eligible without requirement for prospective genetic profiling on the basis of very high prevalence of cancer related
alterations in the tumor suppressor genes (eg, TP53 and RB1) in this population.
c. For subjects with STS, and any others for whom genetic profiling is performed prospectively, eligibility will be determined by the sponsor's
review of genetic abnormalities detected in genes in the following categories:
a) Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as RB1, TP53, etc. For relevant cancers, positive
human papilloma virus (HPV) status is also considered for eligibility.
b) The DNA damage response pathway including ATM, BRCA1, BRCA2, mismatch repair genetic alterations and/or high microsatellite instability
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, CCNE1, etc.
d. For subjects with anogenital cancer, known HPV positive status will confer eligibility without requirement for prospective genetic profiling. If
HPV status is not known or not positive, genetic profiling (or HPV testing where appropriate) may be performed prospectively to determine
eligibility. Subjects with cervical cancer or squamous cell carcinoma of the anus are eligible without requirement for prospective genetic
profiling based on the very high prevalence of HPV positivity in these populations
11) Subjects must meet one of the following criteria:
a. HGSOC, defined by the following:
i. Histologically confirmed high-grade serous ovarian, fallopian tube, or primary peritoneal cancer.
ii. Platinum-resistant or refractory disease or intolerance of platinum therapy.
b. Small Cell Lung Cancer
i. Must have received at least 1 but no more than 3 prior regimens for advanced disease, unless approved otherwise for the sponsor
c. Soft Tissue Sarcoma
i. Including undifferentiated pleiomorphic sarcoma / malignant fibrous histiocytoma (MFH) (including high-grade spindle cell sarcoma / pleomorphic liposarcomas), leiomyosarcoma, and dedifferentiated liposarcomas. Other types of STS may be eligible with sponsor's approval
ii. Must have received at least 1 but no more than 3 prior regimens for advanced disease, unless approved otherwise for the sponsor.
d. Cervical/Anogenital Cancer
i. Including all cervical carcinoma and advanced / metastatic squamous cell carcinoma of the anus, penis, vagina, and vulva
ii. Must have received at least 1 but no more than 3 prior regimens for advanced disease, unless approved otherwise for the sponsor
|
|
| E.4 | Principal exclusion criteria |
1. Have received prior or current anticancer therapy within the noted time periods prior to receiving SRA737 or have recovered from toxicity consistent with exclusion criterion 5:
a) Radiotherapy (except for symptom control and where the lesions will not be used as measurable disease), chemotherapy, therapy with poly ADP ribose polymerase (PARP) inhibitors, other targeted therapies, or other IMPs within 2 weeks
b) Nitrosoureas or Mitomycin C within 6 weeks
c) Any prior treatment with a Chk1 inhibitor, or prior treatment with an ATR inhibitor within 6 months.
2) No more than 3 previous treatment regimens for advanced disease (not applicable to HGSOC expansion cohort), unless otherwise approved by sponsor. Prior gemcitabine therapy is permitted as previous therapy.
3) Other malignancies within the past 2 years with the exception of adequately treated tumors that are associated with an expected 5 year disease-free survival of ≥ 95%.
4) If, in the opinion of the investigator, the subject is highly likely to experience clinically significant myelosuppression, based on previous experience with chemotherapy.
5) 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’s Medical Monitor should not exclude the subject.
6) History of allergy to gemcitabine.
7) New or progressing brain metastases. Subjects with brain metastases that have been asymptomatic and radiologically stable over an 8-week period and have not been treated with steriods during that time may be included with approval from the sponsor.
8) Women of childbearing potential (WOCBP) or women who are already pregnant or lactating. However, those subjects who have a negative serum or urine pregnancy test before enrollment and agree to use 2 forms of contraception or agree to sexual abstinence, effective from the first administration of SRA737, throughout the trial and for 6 months afterwards are considered eligible.
9) Male subjects with partners of child bearing potential, unless they agree to take measures not to father children by using a barrier method of contraception defined, effective 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.
10) Major surgery from which the subject has not yet recovered.
11) At high medical risk because of nonmalignant systemic disease including active uncontrolled infection.
12) Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus.
13) 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, unless approved by the sponsor.
14) Prior bone marrow transplant or have had extensive radiotherapy to greater than 25% of bone marrow within the previous 8 weeks.
15) Peanut allergy (unless this restriction is removed by the sponsor).
16) QTcF > 450 msec in adult males and > 470 msec in adult females.
17) 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).
18) Not able to swallow capsules without chewing or crushing.
19) 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 would be acceptable.
20) 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 adverse event (AE) to SRA737, cisplatin, and/or gemcitabine, 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. |
|
| 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 continues for 30 days after the last administration of the trial IMP or until the patient starts another anti-cancer therapy. Monthly follow up of AEs and SAEs considered drug-related.
2) At the end of the dose escalation phase.
3) At the end of the trial. |
|
| E.5.2 | Secondary end point(s) |
1) Plasma concentration-time profiles of SRA737 based on PK parameters including but not limited to AUCinf, AUCtau, Cmin, Cmax, time to reach Cmax (Tmax), t½.
2) ORR as measured by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). Duration of response (DOR). Disease control rate (DCR). Time to response (TTR). PFS. Time to Progression (TTP). OS.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) SRA737 PK: 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 Day 2 (Stage 1) or Day 9 (Stage 2). An additional sample will be taken on Day 1 prior to chemotherapy dosing.
Gemcitabine & Cisplatin PK: Sample will be taken at the end of the gemcitabine infusion on Day 1 and then up to 6 further samples over a 24 - 48 hour time period.
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 | No |
| 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 | 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.8.3 |
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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 final long-term follow-up visit (whichever is the latter). |
|
| 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 | 7 |
| 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 | 7 |
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