Advanced Solid Tumor, Breast Cancer, Small-cell Lung Cancer, Pancreatic Cancer
Conditions
Brief summary
The study consists of 2 parts. Part 1 is dose escalation and will first administer SY-5609 alone to participants with select advanced solid tumors and then in combination with fulvestrant to participants with HR positive, HER2-negative breast cancer. Part 2 is a dose expansion and will first administer SY-5609 in combination with gemcitabine and then SY-5609 in combination with gemcitabine and nab-paclitaxel in participants with pancreatic ductal adenocarcinoma (PDAC) .
Interventions
DRUGSY-5609
An oral CDK7 Inhibitor
DRUGFulvestrant
Estrogen receptor antagonist
DRUGGemcitabine
Nucleoside metabolic inhibitor
DRUGNab-paclitaxel
Taxane-type chemotherapy
Sponsors
Syros Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years 2. Advanced Solid Tumors for which standard curative or palliative measures do not exist or are no longer effective (Group 1 only). 3. Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. Participants must have failed prior treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor in combination with hormonal therapy in a previous line of therapy (Group 2 only). 4. Participants with histologically or cytologically confirmed PDAC with measurable metastatic lesion(s) (Groups 3 and 4 only). 5. Participants must have at least 1 measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 6. All toxicities (except alopecia) from prior cancer treatments must have resolved to ≤ Grade 1 before enrollment. 7. For women of childbearing potential (WCBP): negative serum β human chorionic gonadotropin pregnancy test within 1 week before the first dose of SY 5609 8. Adequate organ and marrow function 9. Participants must be willing and able to comply with all aspects of the protocol 10. Participants must provide written informed consent before any study-specific screening procedures. 11. Albumin ≥ 3.0 grams/deciliters (g/dL) (Groups 3 and 4 only).
Exclusion criteria
1. Chemotherapy or limited field radiotherapy within 2 weeks, wide field radiotherapy within 4 weeks, or nitrosoureas or mitomycin C within 6 weeks before entering the study 2. Major surgery within 2 weeks before starting the study treatment, or not recovered to baseline status from the effects of surgery received \> 2 weeks prior 3. Received any other investigational agents within 4 weeks before enrollment, or \< 5 half-lives since completion of previous investigational therapy, whichever is shorter 4. Received previous noncytotoxic, US Food and Drug Administration-approved anticancer agent within previous 2 weeks, or \< 5 half-lives since completion of previous therapy, whichever is shorter 5. Known brain metastases or carcinomatous meningitis 6. Immunocompromised participants with increased risk of opportunistic infections 7. Participants with known active or chronic hepatitis B or active hepatitis C infection. Participants with a history of hepatitis C virus (HCV) infection who have completed curative therapy for HCV at least 12 weeks before Screening and have a documented undetectable viral load at Screening are eligible for enrollment. 8. Baseline QT interval corrected (QTc) with Fridericia's method \> 480 milliseconds • NOTE: criterion does not apply to participants with a right or left bundle branch block (QTc interval) 9. Female participants who are pregnant or breastfeeding 10. History of clinically significant cardiac disease or clinically relevant uncontrolled cardiac risk factors 11. Uncontrolled intercurrent illness. 12. Poorly controlled ascites requiring paracentesis within 1 month prior to entering the study. (Groups 3 and 4 only)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Groups 1 and 2: Dose-Limiting Toxicity of SY-5609 | Up to 28 days after first administration |
| Groups 1 and 2: Number of Participants With Treatment Emergent Adverse Events | From Baseline up to 30 days after last dose of study drug (up to 1 year) |
| Groups 3 and 4 (Safety Lead-ins): Number of Participants With Dose-Limiting Toxicity | Up to 28 days after first administration |
| Groups 3 and 4 (Safety Lead-ins): Number of Participants With TEAEs | From Baseline up to 30 days after last dose of study drug (up to 1 year) |
| Groups 3 and 4 (Expansions): Progression Free Survival | Up to 1 year |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Groups 1 and 2: Time of Maximum Plasma Concentration (Tmax) of SY-5609 | Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days) | — |
| Groups 1 and 2: Minimum or Trough Plasma Concentration (Cmin) of SY-5609 | Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days) | — |
| Groups 1 and 2: Time of Minimum or Trough Plasma Concentration (Tmin) of SY-5609 | Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days) | — |
| Groups 3 and 4 (Safety Lead-ins): Progression Free Survival | Up to 1 year | — |
| Groups 3 and 4 (Safety Lead-ins): Objective Response Rate (ORR) | Up to 1 year | ORR is defined as the proportion of participants who achieve complete response (CR) and partial remission (PR) (as determined by the investigator). |
| Groups 3 and 4 (Safety Lead-ins): Complete Response/Remission (CR) Rate | Up to 1 year | CR rate is defined as proportion of participants who achieve CR (as determined by the investigator). |
| Groups 3 and 4 (Safety Lead-ins): Disease Control Rate | Up to 1 year | — |
| Groups 1 and 2: Area Under The Concentration Versus Time Curve of SY-6509 | Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days) | — |
| Groups 3 and 4 (Safety Lead-ins): Duration of Response | Up to 1 year | Duration of response is defined as duration from the date of first documented evidence of response to the date of relapse of disease (as determined by the investigator), or death due to any cause, whichever occurs first. |
| Groups 3 and 4 (Expansions): Objective Response Rate | Up to 1 year | ORR is defined as the proportion of participants who achieve CR and partial remission (PR) (as determined by the investigator). |
| Groups 3 and 4 (Expansions): Complete Response Rate | Up to 1 year | CR rate is defined as proportion of participants who achieve CR (as determined by the investigator). |
| Groups 3 and 4 (Expansions): Disease Control Rate | Up to 1 year | — |
| Groups 3 and 4 (Expansions): Time to Response | Up to 1 year | Time to response is defined as the duration from the date of randomization to the date of the first documented evidence of response as determined by the investigator. |
| Groups 3 and 4 (Expansions): Duration of Response | Up to 1 year | Duration of response is defined as duration from the date of first documented evidence of response to the date of relapse of disease (as determined by the investigator), or death due to any cause, whichever occurs first. |
| Groups 3 and 4 (Safety Lead-ins): Time to Response | Up to 1 year | Time to response is defined as the duration from the date of randomization to the date of the first documented evidence of response as determined by the investigator. |
| Groups 1 and 2: Apparent Clearance of SY-5609 | Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days) | — |
| Groups 1 and 2: Apparent Volume of Distribution of SY-5609 | Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days) | — |
| Groups 1 and 2: Elimination Half-Life of SY-5609 | Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days) | — |
| Groups 1 and 2: Maximum Plasma Concentration (Cmax) of SY-5609 | Predose, 0.5, 1, 2, 4, 6, 8 hours postdose on Day 1 and 4 or 15 of Cycle 1; 24 hours predose on Day 2 and 5 of Cycle 1; 24 hours predose on Day 1 of Cycle 2, 3 and 4 (Each Cycle=28 days) | — |
Countries
United States
Outcome results
None listed