Advanced Solid Tumors or Non-Hodgkin's Lymphoma (NHL)
Conditions
Keywords
Replication stress, Advanced solid tumors, CCNE1, TP53, BRCA1, BRCA2, MYC, RAD50, Fanconi anemia, Cell cycle, Metastatic Colorectal Cancer, Platinum-Resistant or Intolerant High Grade Serious Ovarian Cancer, Advanced Non-Small Cell Lung Cancer, Metastatic Castration-Resistant Prostate Cancer, Head and Neck Squamous Cell Carcinoma, Squamous Cell Carcinoma of the Anus, Phase 1, Phase 2, Dose escalation, Chk1 inhibitor, Checkpoint kinase 1, Synthetic lethality, Next-Generation Sequencing, Genetic biomarkers
Brief summary
The purpose of this clinical study is to establish the safety profile, determine the maximum tolerated dose (MTD) and recommend a Phase 2 dose and schedule of SRA737; and to evaluate the efficacy of SRA737 in prospectively-selected subjects with genetically-defined tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to checkpoint kinase 1 (Chk1) inhibition via synthetic lethality. Specific cancer indications that frequently harbor these genetic mutations will be studied.
Detailed description
SRA737 is a potent, highly selective, orally bioavailable small molecule inhibitor of Chk1, a key regulator of cell cycle progression and the DNA Damage Response (DDR) replication stress response. In cancer cells, intrinsic replication stress (RS) is induced by factors such as oncogenes (e.g., CCNE1 or MYC), genetic mutations in DNA repair machinery (e.g. BRCA1 or FANCA), genetic mutations leading to a dysregulated cell cycle (e.g., TP53 or RAD50) or other genomic alterations. This replication stress results in persistent DNA damage and genomic instability, leading to an increased dependency on Chk1 for survival. Targeted inhibition of Chk1 by SRA737 may therefore be synthetically lethal to cancer cells with elevated intrinsic RS. This study has been designed to: establish the safety profile; determine the pharmacokinetic profile; identify the optimal dose, schedule, and MTD; obtain preliminary evidence of activity; and evaluate SRA737's efficacy in prospectively-selected subjects with tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to Chk1 inhibition via synthetic lethality. This clinical study consists of two phases, a Dose Escalation Phase 1 portion and a Cohort Expansion Phase 2 portion. In the Dose Escalation Phase 1 portion, cohorts consisting initially of a single subject will receive escalating doses of SRA737, administered orally on a continuous daily dosing schedule in 28-day cycles. Once an SRA737-related Grade 2 toxicity is observed in a dose escalation cohort during Cycle 1, that cohort will be expanded to 3 to 6 subjects, and subsequent dose level cohorts will follow a rolling 6 design until the MTD has been identified. In the Cohort Expansion Phase 2 portion, subjects with genetically-defined tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to Chk1 inhibition will be prospectively enrolled into six indication-specific cohorts to explore the preliminary efficacy of SRA737. Subjects must have advanced or metastatic disease of one of the following types: * castration-resistant prostate cancer (mCRPC); * high grade serous ovarian cancer (HGSOC) without CCNE1 gene amplification; * HGSOC with CCNE1 gene amplification (or alternative genetic alteration with similar functional effect); * non-small cell lung cancer (NSCLC); * head and neck squamous cell carcinoma (HNSCC) or squamous cell carcinoma of the anus (SCCA); and * colorectal cancer (mCRC). To qualify for enrolment in the Cohort Expansion Phase 2 portion, the subject's tumor must have a confirmed combination of mutations which are expected to confer sensitivity to Chk1 inhibition, determined by the Sponsor's review of genetic abnormalities detected in the following categories: * Oncogenic drivers such as CCNE1 or MYC, etc. * Genes involved in the DNA repair process including BRCA1, BRCA2, FANC genes, mismatch repair (MMR) genetic alterations and/or high microsatellite instability. * Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as TP53, RAD50, etc. For patients with HNSCC or SCCA, positive human papilloma virus (HPV) status is also considered for eligibility. * Genetic indicators of replicative stress such as gain of function/amplification of CHEK1, ATR or other related genes. Tumor genetics will be prospectively determined using Next-Generation Sequencing.
Interventions
DRUGSRA737
SRA737 will be administered orally on each day of a 28-day cycle. Subjects will receive a single dose of SRA737 between 4 to 7 days prior to starting the first cycle for PK profiling. Subjects can continue taking SRA737 if they are receiving clinical benefit and able to safely take the drug and follow the requirements of the study.
Sponsors
Sierra Oncology LLC - a GSK company
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. For Dose Escalation Only: any locally advanced or metastatic, histologically or cytologically proven solid tumor or NHL, relapsed after or progressing despite conventional treatment 2. Life expectancy of at least 12 weeks 3. World Health Organization (WHO) performance status of 0-1 4. Must meet select hematological and biochemical laboratory indices 5. Archival tumor tissue or accessible tumor and willingness to consent to a biopsy Expansion Only: 1. Any locally advanced or metastatic malignancy of the following types for which no other conventional therapy is considered appropriate: * Metastatic Colorectal Cancer (CRC) * Platinum-resistant or intolerant High Grade Serious Ovarian Cancer (HGSOC) * Advanced Non-Small Cell Lung Cancer (NSCLC) * Metastatic Castration-Resistant Prostate Cancer (mCRPC) * Head and Neck Squamous Cell Carcinoma (HNSCC) or squamous cell carcinoma of the anus (SCCA). * Eligibility may be further restricted by the select number of prior regimens specific to each indication 2. Measurable disease per RECIST v1.1, or for mCRPC, evaluable disease per any of the following: * Measurable disease per RECIST v1.1 * Increasing PSA * Circulating tumor cell (CTC) count of 5 or more cells per 7.5 ml of blood 3. Tumor tissue or ctDNA evidence that subject's 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: * Oncogenic drivers such as MYC, CCNE1, etc. * Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as RAD50, TP53, etc. For patients with NHSCC or SCCA, positive HPV status is also considered for eligibility. * The DDR pathway including BRCA1, BRCA2 and FANC. For patients with CRC, MMR genetic alterations and/or high microsatellite instability are also considered for eligibility. * Genetic indicators of replicative stress such as gain of function/amplification of Chk1 or ATR or other related gene. Key
Exclusion criteria
1. Received the following prior or current anticancer therapy: * Radiotherapy within the last 6 weeks * Endocrine therapy during the previous 4 weeks * Chemotherapy during the previous 4 weeks * Immunotherapy during the previous 6 weeks * Nitrosoureas or Mitomycin C during the previous 6 weeks * Other Investigational Medicinal Product during the 4 weeks before treatment * 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, except for adequately treated tumors 3. Ongoing toxic manifestations of previous treatments greater than NCI-CTCAE Grade 1 4. For Dose Escalation: new or progressing brain metastases. For Cohort Expansion: present or prior brain metastases 5. High medical risk because of nonmalignant systemic disease 6. Serologically positive for hepatitis B, hepatitis C or HIV 7. Serious cardiac condition, left ventricular ejection fraction \< 45% at baseline, history of cardiac ischemia within the past 6 months, or prior history of cardiac arrhythmia requiring treatment 8. Prior bone marrow transplant or extensive radiotherapy to greater than 25% of bone marrow within 8 weeks 9. Peanut allergy 10. QTcF\> 450 msec in adult males and \> 470 msec in adult females 11. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of SRA737 12. Inability to swallow capsules without chewing or crushing 13. Is a participant or plans to participate in another interventional clinical trial 14. Any other condition which in the Investigator's opinion would not make the subject a good candidate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Adverse Events as Assessed by CTCAE 4.03 | Up to 30 days after last dose of SRA737 | Treatment-emergent adverse events (TEAEs) were reported until the safety Follow up (SFU) visit, 30 days after the last dose of SRA737 or prior to the initiation of a new anticancer treatment, whichever came first. |
| Maximum Tolerated Dose of SRA737 | Cycle 1 (28 days) in the Dose Escalation Phase | The highest dose at which ≤ 33% of subjects have a dose limiting toxicity (DLT) in a cohort of up to 6 subjects. |
| Recommended Phase 2 Dose of SRA737 | Up to 30 days after last dose of SRA737 | The RP2D and schedule were defined by the Cohort Review Committee at the end of the study and took all clinically relevant toxicity, PK and PDn data into account. The RP2D was to be a dose equal to or less than the MTD for the selected schedule. |
| Disease Control Rate (DCR) of SRA737 | Radiographic tumor assessments were performed every 2 cycles of therapy. | The disease control rate (DCR) was defined as the number of subjects achieving complete response (CR) + partial response (PR) + stable disease (SD) per RECIST 1.1 criteria. Since no subjects achieved CR or PR in this study, the DCR represents the proportion of subjects in each group who achieved SD. |
| Time to Progression (TTP) | Radiographic tumor assessments were performed every 2 cycles of therapy. Follow-up assessments were made every 16 weeks for subjects who had not progressed and had not initiated new anticancer therapy. | Time to progression (TTP) was defined as the time from Cycle 1 Day 1 to the earliest date of radiographic disease progression per RECIST 1.1, or if the subject did not experience disease progression, to the last imaging assessment. TTP was analyzed using the K-M method. |
| Progression Free Survival (PFS) | Radiographic tumor assessments were performed every 2 cycles of therapy. Follow-up assessments were made every 16 weeks for subjects who had not progressed and had not initiated new anticancer therapy. | Progression free survival (PFS) was defined as time from Cycle 1 Day 1 to the earliest date of radiographic disease progression per RECIST 1.1 or death, whichever happened first. Censoring rules are defined in the SAP. PFS was analyzed using the K-M method. |
| Overall Survival (OS) | Follow-up assessments were made every 16 weeks for subjects who had not progressed and had not initiated new anticancer therapy. | Overall survival (OS) was defined as time from Cycle 1 Day 1 to the date of death (or date last known to be alive). OS was analyzed using the K-M method. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Colorectal Cancer Metastatic colorectal cancer (CRC) defined as histologically and/or cytologically confirmed CRC, and must have received at least 1 prior regimen for advanced/metastatic disease. | 32 |
| High Grade Serous Ovarian Cancer High grade serous ovarian cancer (HGSOC) defined as histologically confirmed high grade serous ovarian, fallopian tube or primary peritoneal cancer who were recurrent platinum intolerant, or with platinum resistant disease defined as radiological evidence of disease progression within 6 months of the last receipt of platinum based chemotherapy. | 37 |
| Non Small Cell Lung Cancer Advanced non small cell lung cancer (NSCLC) defined as locally advanced and recurrent or metastatic, histologically confirmed NSCLC, and must have received at least 1 prior regimen for advanced/metastatic disease. | 10 |
| Metastatic Other Tumor Type Castration Resistant Prostate Cancer Metastatic castration resistant prostate cancer (mCRPC) defined as histologically or cytologically confirmed adenocarcinoma of the prostate that has progressed after androgen deprivation therapy. | 16 |
| Head and Neck Squamous Cell Carcinoma Histologically confirmed HNSCC from any primary site; 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. | 4 |
| Other Tumor Type Any locally advanced or metastatic, histologically or cytologically proven solid tumor or NHL, that had relapsed after or progressing despite conventional treatment for which no conventional therapy was considered appropriate by the investigator or had been declined by the subject. | 8 |
| Total | 107 |
Baseline characteristics
| Characteristic | Colorectal Cancer | Total | Other Tumor Type | Head and Neck Squamous Cell Carcinoma | Metastatic Other Tumor Type Castration Resistant Prostate Cancer | Non Small Cell Lung Cancer | High Grade Serous Ovarian Cancer |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 61.3 years STANDARD_DEVIATION 12.05 | 62.2 years STANDARD_DEVIATION 10.04 | 58.4 years STANDARD_DEVIATION 6.46 | 63.0 years STANDARD_DEVIATION 6.06 | 68.3 years STANDARD_DEVIATION 6.76 | 64.4 years STANDARD_DEVIATION 9.11 | 60.6 years STANDARD_DEVIATION 9.81 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 99 Participants | 8 Participants | 4 Participants | 15 Participants | 10 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 8 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 29 Participants | 99 Participants | 8 Participants | 4 Participants | 13 Participants | 10 Participants | 35 Participants |
| Region of Enrollment United Kingdom | 32 participants | 107 participants | 8 participants | 4 participants | 16 participants | 10 participants | 37 participants |
| Sex: Female, Male Female | 14 Participants | 61 Participants | 4 Participants | 0 Participants | 0 Participants | 6 Participants | 37 Participants |
| Sex: Female, Male Male | 18 Participants | 46 Participants | 4 Participants | 4 Participants | 16 Participants | 4 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 18 / 107 |
| other Total, other adverse events | 106 / 107 |
| serious Total, serious adverse events | 48 / 107 |
Outcome results
Primary
Disease Control Rate (DCR) of SRA737
The disease control rate (DCR) was defined as the number of subjects achieving complete response (CR) + partial response (PR) + stable disease (SD) per RECIST 1.1 criteria. Since no subjects achieved CR or PR in this study, the DCR represents the proportion of subjects in each group who achieved SD.
Time frame: Radiographic tumor assessments were performed every 2 cycles of therapy.
Population: The Response Evaluable Population (REP) included all enrolled subjects who satisfy all of the following conditions:~1. Measurable disease and assessment at baseline~2. Received at least 75% of 1 cycle of study medication, based on dosing information~3. At least one post baseline disease assessment OR discontinued treatment due to AE or disease progression or death
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Evaluable Population | Disease Control Rate (DCR) of SRA737 | 8 Participants |
| High Grade Serous Ovarian Cancer | Disease Control Rate (DCR) of SRA737 | 11 Participants |
| Non Small Cell Lung Cancer | Disease Control Rate (DCR) of SRA737 | 3 Participants |
| Metastatic Other Tumor Type Castration Resistant Prostate Cancer | Disease Control Rate (DCR) of SRA737 | 8 Participants |
| Head and Neck Squamous Cell Carcinoma | Disease Control Rate (DCR) of SRA737 | 3 Participants |
Primary
Maximum Tolerated Dose of SRA737
The highest dose at which ≤ 33% of subjects have a dose limiting toxicity (DLT) in a cohort of up to 6 subjects.
Time frame: Cycle 1 (28 days) in the Dose Escalation Phase
Population: In order to determine the MTD, a total of 18 subjects were enrolled in the dose escalation phase of the study in 9 dosage cohorts. All subjects receiving at least 75% of planned doses of SRA737 within Cycle 1 and those subjects receiving less than these planned doses of SRA737 due to DLT were considered evaluable for dose review decisions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Evaluable Population | Maximum Tolerated Dose of SRA737 | 1000 mg QD |
Primary
Number of Subjects With Adverse Events as Assessed by CTCAE 4.03
Treatment-emergent adverse events (TEAEs) were reported until the safety Follow up (SFU) visit, 30 days after the last dose of SRA737 or prior to the initiation of a new anticancer treatment, whichever came first.
Time frame: Up to 30 days after last dose of SRA737
Population: As specified in the Statistical Analysis Plan, the frequency of each AE was evaluated in the overall Safety Evaluable Population rather than by tumor type subgroups with the intention of displaying the overall safety profile of SRA737 in advanced solid tumors. The Safety Evaluable Population includes all enrolled subjects who receive at least 1 dose of SRA737.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Evaluable Population | Number of Subjects With Adverse Events as Assessed by CTCAE 4.03 | 106 Participants |
Primary
Overall Survival (OS)
Overall survival (OS) was defined as time from Cycle 1 Day 1 to the date of death (or date last known to be alive). OS was analyzed using the K-M method.
Time frame: Follow-up assessments were made every 16 weeks for subjects who had not progressed and had not initiated new anticancer therapy.
Population: The Response Evaluable Population (REP) included all subjects who satisfy the following conditions:~1. Measurable disease and assessment at baseline~2. Received at least 75% of 1 cycle of study medication, based on dosing information~3. At least 1 post baseline disease assessment OR discontinued treatment due to AE or disease progression or death Note: The median OS was not estimated in the mCRPC, HNSCC, or Other tumor type subgroups due to insufficient number of participants with events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Evaluable Population | Overall Survival (OS) | 5.72 months |
| High Grade Serous Ovarian Cancer | Overall Survival (OS) | 6.93 months |
| Non Small Cell Lung Cancer | Overall Survival (OS) | 6.08 months |
| Metastatic Other Tumor Type Castration Resistant Prostate Cancer | Overall Survival (OS) | NA months |
| Head and Neck Squamous Cell Carcinoma | Overall Survival (OS) | NA months |
| Other Tumor Type | Overall Survival (OS) | NA months |
| Overall | Overall Survival (OS) | 6.93 months |
Primary
Progression Free Survival (PFS)
Progression free survival (PFS) was defined as time from Cycle 1 Day 1 to the earliest date of radiographic disease progression per RECIST 1.1 or death, whichever happened first. Censoring rules are defined in the SAP. PFS was analyzed using the K-M method.
Time frame: Radiographic tumor assessments were performed every 2 cycles of therapy. Follow-up assessments were made every 16 weeks for subjects who had not progressed and had not initiated new anticancer therapy.
Population: The Response Evaluable Population (REP) included all enrolled subjects who satisfy all of the following conditions:~1. Measurable disease and assessment at baseline~2. Received at least 75% of 1 cycle of study medication, based on dosing information~3. At least one post baseline disease assessment OR discontinued treatment due to AE or disease progression or death
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Evaluable Population | Progression Free Survival (PFS) | 1.84 months |
| High Grade Serous Ovarian Cancer | Progression Free Survival (PFS) | 1.94 months |
| Non Small Cell Lung Cancer | Progression Free Survival (PFS) | 1.76 months |
| Metastatic Other Tumor Type Castration Resistant Prostate Cancer | Progression Free Survival (PFS) | 3.02 months |
| Head and Neck Squamous Cell Carcinoma | Progression Free Survival (PFS) | 3.55 months |
Primary
Recommended Phase 2 Dose of SRA737
The RP2D and schedule were defined by the Cohort Review Committee at the end of the study and took all clinically relevant toxicity, PK and PDn data into account. The RP2D was to be a dose equal to or less than the MTD for the selected schedule.
Time frame: Up to 30 days after last dose of SRA737
Population: All 107 subjects treated in the study were included in the review of toxicity, PK and PDn, data in order to determine the RP2D. All clinically relevant toxicity, PK and PDn data up to 30 days after last dose of SRA737 were taken into account.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Evaluable Population | Recommended Phase 2 Dose of SRA737 | 800 mg QD |
Primary
Time to Progression (TTP)
Time to progression (TTP) was defined as the time from Cycle 1 Day 1 to the earliest date of radiographic disease progression per RECIST 1.1, or if the subject did not experience disease progression, to the last imaging assessment. TTP was analyzed using the K-M method.
Time frame: Radiographic tumor assessments were performed every 2 cycles of therapy. Follow-up assessments were made every 16 weeks for subjects who had not progressed and had not initiated new anticancer therapy.
Population: The Response Evaluable Population (REP) included all enrolled subjects who satisfy all of the following conditions:~1. Measurable disease and assessment at baseline~2. Received at least 75% of 1 cycle of study medication, based on dosing information~3. At least one post baseline disease assessment OR discontinued treatment due to AE or disease progression or death
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Evaluable Population | Time to Progression (TTP) | 1.87 months |
| High Grade Serous Ovarian Cancer | Time to Progression (TTP) | 1.94 months |
| Non Small Cell Lung Cancer | Time to Progression (TTP) | 1.87 months |
| Metastatic Other Tumor Type Castration Resistant Prostate Cancer | Time to Progression (TTP) | 3.02 months |
| Head and Neck Squamous Cell Carcinoma | Time to Progression (TTP) | 3.87 months |