A Study of GFH009 in Patients With Hematologic Malignancies

Study Overview
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Brief Summary
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GFH009 is a potent and highly selective CDK9 inhibitor. To assess the safety, tolerability, and antitumor activity of single agent GFH009, this study consists of two dose escalation groups in patients with relapsed/refractory acute myeloid leukemia (Group 1) and in patients with relapsed/refractory lymphomas (Group 2). The safety, tolerability, and antitumor activity of GFH009 in combination with venetoclax and azacitidine in patients with relapsed/refractory acute myeloid leukemia (AML) who have relapsed on or are refractory to venetoclax-based regimens will also be assessed (Group 3).

Official Title
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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

Conditions
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Hematologic Malignancies

Intervention / Treatment
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* Drug: GFH009
* Drug: GFH009
* Drug: GFH009, venetoclax, azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients with cytological or histologically confirmed relapsed or refractory hematologic malignancies (AML, CLL/SLL and lymphoma) Lymphoma: At least one measurable or evaluable lesion as defined by the Lugano (2014) response criteria. Patients must have received at least 2 prior lines of systemic therapy. AML (only for Group 3): Patients relapsed on or refractory to venetoclax containing regimens. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) except for patients with Gilbert's syndrome, who are included if total bilirubin is < 3 × ULN or if direct bilirubin is < 1.5 × ULN. • Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 × ULN. For those with hepatic metastases, AST and ALT ≤ 5 × ULN. Amylase ≤1.5 × ULN 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 women of childbearing potential, must consent to use highly effective methods (i.e, 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 Groups 1 or 2, and 6 months if enrolled in Group 3. Men with a partner of childbearing potential, must consent to use two highly effective methods of contraception during GFH009 treatment and for an additional 90 days after the last administration of study drug. Exclusion Criteria Patients with bulky disease (≥ 10 cm) who require cytoreductive therapy. Symptomatic central nervous system metastases or primary lymphoma such as primary CNS lymphoma, leptomeningeal disease, or spinal cord compression. Patients with asymptomatic CNS metastases who are radiologically and neurologically stable ≥ 4 weeks following CNS-directed therapy and are on a stable or decreasing dose of corticosteroids are eligible for study entry. 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), LVEF < 50% as determined by MUGA scan or echocardiogram (ECHO), (if just with historical occasional low LVEF but without any symptoms or relevant medical history, and the LVEF at screening is > 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 with a baseline cardiac biomarker abnormality (CKMB/cTnI) will be excluded. Patients with hypereosinophilic syndrome defined as eosinophil counts in peripheral blood of ≥1,500/µ. Concurrent malignancy within 5 years (for AML patients, 2 years) prior to entry other than adequately treated cervical carcinoma-in-situ, localized squamous cell cancer of the skin, basal cell carcinoma, prostate cancer not requiring treatment, ductal carcinoma in situ of the breast, and superficial non-muscle invasive urothelial carcinoma (excluding T1 lesions and CIS). Active hepatitis B or hepatitis C virus infection. History of HIV infection or HIV positive at screening. Concomitant medications that are strong CYP3A4 inhibitors and strong inducers within 7 days of 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1. Dose escalation in patients with relapsed/refractory AML<br> | Drug: GFH009<br>* In the dose escalation part, the dose levels will be escalated following the Bayesian optimal interval (BOIN) design. In the expansion part, patients will be assigned based on tumor type(s).<br>|
| Experimental: Group 2. Dose escalation in patients with relapsed/refractory CLL/SLL or lymphoma<br> | Drug: GFH009<br>* In the dose escalation part, the dose levels will be escalated following the Bayesian optimal interval (BOIN) design. In the expansion part, patients will be assigned based on tumor type(s).<br>|
| Experimental: AML Patients relapsed/refractory to vene and who will be treated with GFH in combo with vene & aza<br>Group 3. Patients with relapsed/refractory AML who have relapsed on or are refractory to venetoclax-based regimens | Drug: GFH009, venetoclax, azacitidine<br>* Group 3. Patients with relapsed/refractory AML who have relapsed on or are refractory to venetoclax-based regimens<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of GFH009: Dose Limiting Toxicities (DLTs) | The incidence of DLTs | 21 to 28 days | 
| Safety and Tolerability of GFH009: adverse events (AEs) | The incidence and severity of all AEs | approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameter AUC0-t | Area under the plasma concentration-time curve (from zero to the time of the last measurable concentration) | approximately 3 months | 
| PK parameter AUC0-∞ | Area under the plasma concentration-time curve (from zero to infinity) | approximately 3 months | 
| Efficacy: CR |  | 2 years | 
| Efficacy: DOR |  | 2 years | 
| Efficacy: PFS |  | 2 years | 
| Efficacy:OS |  | 2 years | 
| PK parameter Cmax |  | approximately 3 months | 
| PK parameter Tmax |  | approximately 3 months | 
| PK parameter Ctrough |  | approximately 3 months | 
| PK parameter t½ |  | approximately 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute myeloid leukemia, lymphoma, relapsed, refractory, CDK9 inhibitor, GFH009, venetoclax, azacitidine