Clinical Trial 24126

• Overview

  Study Title:

  A Phase I/IIa, Open-Label Dose Escalation and Dose Expansion Study of Intravenous GFH009 Single Agent and in Combination with Venetoclax and Azacitidine in Patients with Relapsed/Refractory Hematologic Malignancies and High-Risk Newly Diagnosed AML

  Summary:

  SLS009 (formerly GFH009) is a potent and highly selective CDK9 inhibitor. In this study the safety, tolerability, and antitumor activity of single agent SLS009 are assessed in two dose escalation groups (Group 1 in patients with relapsed/refractory AML, Group 2 in patients with relapse/refractory lymphoma/CLL/SLL). The safety, tolerability, and antitumor activity of SLS009 in combination with venetoclax and azacitidine in patient with relapsed/refractory AML who have relapsed on or are refractory to venetoclax-based regimens are being assessed in five cohorts of the expansion Group 3. Groups 4 and 5 have been added to evaluate efficacy, safety, and tolerability of GFH009 in combination with venetoclax and azacitidine in newly diagnosed AML patients who are less likely to benefit from standard induction treatment with venetoclax plus HMA only regimens.

  Objective:

  Primary Objective: Groups 1, 2 and 3 To evaluate the safety and tolerability of GFH009 single agent in patients with relapsed/refractory (r/r) hematologic malignancies, including acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and lymphoma. To evaluate the safety, tolerability, and efficacy of GFH009 in patients with r/r AML who failed venetoclax containing regimens. To determine the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) of GFH009. Groups 4 and 5 To evaluate the efficacy of GFH009 addition to azacitidine/venetoclax in patients with newly diagnosed AML less likely to benefit from standard azacitidine/venetoclax therapy alone. Secondary Objectives: Groups 1, 2 and 3 To characterize the pharmacokinetic (PK) profile of GFH009 as a single agent and in combination with venetoclax and azacitidine. To characterize the pharmacokinetic (PK) profile of venetoclax in combination with GFH009 and azacitidine. To evaluate preliminary anti-tumor activities of GFH009 as a single agent in r/r AML, and as a single agent in r/r CLL, SLL and lymphoma patients. To evaluate pharmacodynamic (PD) biomarkers of GFH009 including Mcl-1 and c-Myc expression (mRNA level in peripheral blood. For Group 3 only: to evaluate BH3 and flow cytometry profiles of patients receiving combination therapy of GFH009, venetoclax and azacitidine. To evaluate GFH009 Single Agent and in Combination with Venetoclax and Azacitidine Overall Survival (OS). Groups 4 and 5 To evaluate complete remission with incomplete hematologic recovery (CRi) rate, composite complete remission (CRc) rate (CR+CRi), overall response rate (ORR; CR+CRi+MLFS). To evaluate DOR, PFS, and OS of GFH009 in combination with venetoclax and azacitidine. To evaluate safety and tolerability of GFH009 in combination with venetoclax and azacitidine. To evaluate relationship between genomics, transcriptomics, and proteomics and GFH009 efficacy, including but not limited to MCL1 status.

• Treatments

  Therapies:

  BCL-2 inhibitor; Potent and highly selective CDK9 inhibitor; Pyrimidine nucleoside analog

  Medications:

  Azacitidine (); GDC-0199 (Venetoclax); GFH-009 (); Venetoclax ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Male or female ≥ 18 years. For Group 3 Cohorts 4 and 5 only male or female ≥18 years and pediatric patients 12-18 years and ≥40 kg body mass.
  • Written informed consent must be obtained prior to any screening procedures.
  • For AML, acute promyelocytic leukemia (APL) patients are not included in the study.
  • Adequate hepatic function as evidenced by meeting all the following requirements: Total bilirubin ≤ 1.5 × upper limit of normal (ULN) except for patients with Gilbert's syndrome, who are included if total bilirubin is > Measured or calculated (determined by the Cockcroft-Gault equation) serum creatinine clearance (CrCl) ≥ 60 mL/min (glomerular filtration rate can be alternative to CrCl) for adult patients or serum creatinine ≤ 1.5 x ULN; or if serum creatinine > 1.5 x ULN, then serum creatinine clearance (CrCl) ≥ 50 mL/min (estimated by Cockcroft-Gault formula or other appropriate formula) for pediatric patients. Whether the value is calculated by equation or measured directly can be based on institutional standard practice.
  • Amylase ≤ 1.5 × ULN.
  • Eastern cooperative oncology group (ECOG) performance status 0-2.
  • The electrolytes and uric acid level need to be stable judged by investigators for at least 3 days before the first dose of GFH009 (Medical intervention is permitted).
  • For AML and other leukemias: • Peripheral WBC counts > Recovery to grade 0-1 from adverse events related to prior anti-tumor therapy except alopecia, fatigue, > For women of childbearing potential, she must consent to use highly effective methods (e.g., total abstinence, placement of an intrauterine device) of contraception during GFH009 treatment and for an additional 90 days after the last administration of study drug if enrolled in Group 1 and 2, and 6 months enrolled in Group 3.
  • Additional inclusion criteria will apply.

• Exclusion Criteria

  Key Exclusion Criteria
  • Uncontrolled medical conditions such as hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 100 mmHg), a history of hypertensive crisis, or a history of hypertensive encephalopathy.
  • History of previous exposure to any other CDK9 inhibitors.
  • Known hypersensitivity to the study drug or excipients of the preparation or any agent given in association with this study.
  • Severe cardiovascular disease within 6 months of study entry, including any of the following:Clinically significant heart disease such as congestive heart failure requiring treatment (NYHA class III or IV), left ventricular ejection fraction (LVEF) 50%, the subject is eligible), or clinically significant arrythmia. History/evidence of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass graft (CABG), coronary angioplasty, or stenting). Average QTcF ≥ 450 msec (males) or ≥ 470 msec (females) on screening ECG. Moderate or above regurgitation on echocardiogram.
  • Patients with prior treatment with cardiotoxic agents who have experienced drug induced cardiotoxicities during or after treatment, where cardiotoxic agents include but are not limited to anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone); trastuzumab and trastuzumab based ADCs; tyrosine kinase inhibitors (sunitinib, imatinib); alkylating agents (cyclophosphamide).
  • Patients who are on systemic antibiotics are eligible to participate as long as the antibiotics are not expected to have significant DDI with GFH009 (A list of approved concomitant medications will be provided to investigators. If any antibiotic is not included in the approved list, it can be discussed with the sponsor or designated CRO on a case-by-case basis). Active hepatitis B or hepatitis C virus infection. Patients with chronic HBV infection with active disease who meet the criteria for anti HBV therapy have to be on a suppressive antiviral therapy prior to enrollment.
  • Patients with HCV may be enrolled if the HCV is stable, and the patient is not at risk for hepatic decompensation.
  • Patients with known HIV infection except if: They have CD4+ T-cell (CD4+) counts ≥ 350 cells/uL, and No history of AIDS-defining opportunistic infections within the last 12 months preceding screening, and Are on established ART for at least four weeks and have an HIV viral load less than 400 copies/mL prior to enrollment.
  • Concomitant medications that are strong CYP3A4 inhibitors or strong inducers within 7 days prior to the first dose. Avoid consumption of Seville orange (and juice), grapefruit or grapefruit juice, grapefruit hybrids, pomelos, star citrus fruits or St. John's wort within 7 days of first dose.
  • Stroke or intracranial hemorrhage within 6 months.
  • Major surgery within 4 weeks prior to study entry.
  • Pregnant or breast-feeding females.
  • Prior allogeneic stem cell transplant within 6 months of study entry. Patients who received autologous HCT, if considered to be enrolled and must be > 3 months post-transplant and meet hematologic inclusion criteria.
  • Any uncontrolled intercurrent illness or condition that in the judgement of the investigator may endanger the patient.
  • Medications that are known to prolong the QT interval that could not be stopped prior to study entry judged by investigator, except azole antifungal medications in AML patients.
  • Additional exclusion criteria will apply.

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