Business Decision

This study consists of two parts. Part 1 is a dose-escalation/safety evaluation to provisionally identify a dose and regimen of SY-1365 for further evaluation in Part 2.

Following the identification of a recommended dose and regimen from Part 1, the study entered Part 2 to further evaluate safety and the antitumor activity of SY-1365 in patients with select solid tumors, and to confirm target engagement and downstream pathway impact in patients with any solid tumor histology.

This study consists of two parts. Part 1 is a dose-escalation/safety evaluation to identify a dose and regimen for further evaluation in Part 2. SY-1365 will be administered intravenously weekly & twice weekly for 3 weeks of each 4 week cycle. Dose escalation will proceed until the determination of the maximum tolerated dose (MTD) or a recommended dose and regimen for evaluation in Part 2 of the study. Part 1 was concluded in September 2018 with a total of 32 evaluable patients.

Following the identification of a recommended dose and regimen from Part 1, the study entered Part 2 to further evaluate safety and the antitumor activity of SY-1365 in patients with select solid tumors, and to confirm target engagement and downstream pathway impact in patients with any solid tumor histology.

Preliminary anti-tumor activity will be evaluated in up to approximately 102 evaluable patients in Part 2, with SY-1365 administered alone, in combination with carboplatin, or in combination with fulvestrant. Part 2 will consist of five cohorts:

• Cohort 1: approximately 24 patients with advanced ovarian cancer with 3+ previous lines of treatment. Monotherapy
• Cohort 2: approximately 24 patients with relapsed ovarian cancer with previous platinum therapy. SY-1365 + Carboplatin
• Cohort 3: approximately 12 patients with clear cell ovarian cancer. Monotherapy
• Cohort 4: approximately 20-30 patients with biopsy-accessible, advanced solid tumors of any histology. Monotherapy.
• Cohort 5: approximately 12 patients with HR+ metastatic breast cancer post CDK4/6 + hormonal therapy treatment. SY-1365 + fulvestrant.

Overall, the study may enroll up to approximately 137 evaluable patients across dose escalation (Part 1) and expansion cohorts (Part 2, Cohorts 1, 2, 3, 4, and 5).

Inclusion Criteria:

• 18 years of age or older

• Disease status

  • Part 1: any histologically-confirmed metastatic or unresectable solid tumor for which standard curative or palliative measures do not exist or are no longer effective
  • Part 2, Cohorts 1 and 2, all patients must have a histologically-confirmed diagnosis of high grade serous ovarian cancer (including fallopian tube cancer and/or primary peritoneal cancer)
  • Part 2, Cohort 1, patients must have received ≥ 3 prior treatment regimens for ovarian cancer including a platinum-based regimen. Patients whose ovarian cancer harbors a mutation in breast cancer gene (BRCA), either germline or somatic, must have been previously treated with a poly(ADP ribose) polymerase (PARP) inhibitor, or be considered unwilling or ineligible for treatment with a PARP inhibitor
  • Part 2, Cohort 2, patients must have received ≥ 1 prior treatment regimen for ovarian cancer, at least 1 of which is a platinum-based regimen
  • Part 2,Cohort 3, all patients must have a histologically-confirmed diagnosis of clear cell ovarian cancer and must have received ≥ 1 prior treatment regimen for clear cell ovarian cancer, at least 1 of which is a platinum-based regimen.
  • Part 2, Cohort 4, any histologically-confirmed metastatic or unresectable solid tumor for which standard curative or palliative measures do not exist or are no longer effective. Must have accessible tumor tissue and be willing to undergo tumor tissue sampling (biopsies/aspirates) pre-, during, and post-treatment
  • Part 2, Cohort 5, postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer who have failed prior treatment with a CDK 4/6 inhibitor in combination with a hormonal therapy (i.e. aromatase inhibitors, fulvestrant). Treatment failure is based on development of clinical or documented progression during treatment with a CDK4/6 inhibitor in combination with hormonal therapy after ≥ 6 months of therapy. Progression following discontinuation of CDK4/6 treatment due to safety and/or tolerability is not considered as treatment failure for purposes of inclusion criteria. Documentation of HR-positive and HER2-negative status must be available.

• At least 1 measurable lesion by RECIST 1.1

• All toxicities (except alopecia) from prior cancer treatments must have resolved to ≤ Grade 1 or returned to baseline levels prior to enrollment

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

• Life expectancy > 3 months

• Absolute neutrophil count: ≥ 1.5 x 10^9/L

• Platelets: ≥ 100 x 10^9/L

• Hemoglobin: ≥ 9 g/dL

• Total bilirubin ≤ 1.5 x institutional upper limit of normal [ULN]

• AST (SGOT)/ ALT (SGPT): ≤ 3.0 x institutional ULN

• Creatinine ≤ 1.5 x institutional ULN OR creatinine clearance ≥ 60 mL/min by Crockoft-Gault for participants with creatinine levels above institutional normal

• Negative serum pregnancy test for women of child bearing potential

Exclusion Criteria:

• Chemotherapy or limited field radiotherapy within 2 weeks, wide field radiotherapy within 4 weeks, or nitrosoureas or mitomycin C within 6 weeks prior to entering the study
• Major surgery within 2 weeks of starting the study treatment, or not recovered to baseline status from the effects of surgery received > 2 weeks prior
• Received any other investigational agents within 4 weeks prior to enrollment, or < 5 half-lives since completion of previous investigational therapy, whichever is shorter
• Received previous non-cytotoxic, FDA-approved anticancer agent within previous 2 weeks, or < 5 half-lives since completion of previous therapy, whichever is shorter
• Prior exposure to transcriptional kinase family CDK inhibitors, such as the CDK7 and CDK9 inhibitors alvocidib (Flavopiridol), dinaciclib, and seliciclib. Exception: previous exposure to cell cycle CDK inhibitors such as CDK4 and CDK6 (eg, palbociclib) is allowed
• Known brain metastases or carcinomatous meningitis. Exception: previously treated brain metastatic disease that remains stable on MRI ≥ 4 weeks prior to enrollment without steroids or anti-epileptic medications
• History of allergic reactions attributed to compounds of similar chemical composition to SY-1365
• Immunocompromised patients with increased risk of opportunistic infections, including known HIV-positive patients
• Patients with known active Hepatitis B or Hepatitis C infection
• Prior treatment (< 2 weeks before start of SY-1365) with moderate or strong CYP3A4 inducers or strong CYP3A4 inhibitors
• Baseline QT interval corrected with Fridericia's method (QTcF) > 480 ms. NOTE: criterion does not apply to patients with a right or left bundle branch block (QTc interval)
• Significant cardiac risk, including: History of clinically significant cardiac disease or clinically relevant uncontrolled cardiac risk factors
• Uncontrolled intercurrent illness

Part 2 Only:

• Cohorts 1 and 2: Patients with low-grade ovarian cancer (eg, low grade serous, mucinous carcinoma) are not eligible
• Cohort 2: Prior adverse reaction(s) to carboplatin or any medical condition that precludes re-treatment with carboplatin
• Cohort 5: More than 1 prior line of treatment with systemic chemotherapy for advanced/metastatic disease; Advanced/metastatic disease that is symptomatic and/or with visceral spread that are at risk of life-threatening complications in the short term; Contraindication to receiving fulvestrant OR any medical condition that requires a lower dose of fulvestrant at the initiation of therapy