Dose Escalation/ Expansion Study of CA-4948 as Monotherapy in Patients With AML or MDS

Study Overview
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Brief Summary
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This is a multicenter, open-label, Phase 1/2a dose escalation and expansion study of orally administered emavusertib (CA-4948) monotherapy in adult patients with Acute Myelogenous Leukemia (AML) or high risk Myelodysplastic Syndrome (MDS). Patients enrolling in the Phase 1 portion of the study must meet one of the following criteria prior to consenting to the study: R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor R/R AML with spliceosome mutations of SF3B1 or U2AF1 R/R hrMDS with spliceosome mutations of SF3B1 or U2AF1 Number of pretreatments: 1 or 2 The Phase 2a Dose Expansion will be in 3 Cohorts of patients: R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor; R/R AML with spliceosome mutations of SF3B1 or U2AF1; and R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1. All patients above have had ≤ 2 lines of prior systemic anticancer treatment. In previous versions of this protocol there was a Phase 1b portion of the study, in which patients with AML or hrMDS received CA-4948 in combination with venetoclax. This part of the study is no longer open for enrollment.

Detailed Description
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The primary objective of the Phase 1 portion of the study is to determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) for emavusertib in monotherapy in patients with AML, intermediate high risk, high risk MDS based on the safety and tolerability, dose-limiting toxicities (DLTs), and Pharmacokinetic (PK)/Pharmacodynamic (PD) findings. The primary objective of the Phase 1b portion of the study is to determine MTD and RP2D for emavusertib in combination with azacitidine (AZA) in treatment naïve patients with hrMDS or in combination with venetoclax (VEN) in relapsed/ refractory (R/R) patients with AML or high risk myelodysplastic syndrome (hrMDS) after first line treatment based on the safety and tolerability, DLTs and PK and pharmacodynamic findings. Note, this portion of the study is no longer enrolling patients. The primary objective of the Phase 2a portion of the study (emavusertib monotherapy expansion) is to assess anti-cancer activity of CA-4948 at the RP2D in patients with R/R AML with FMS-like tyrosine kinase-3 (FLT-3) mutations, or patients with R/R hrMDS or R/R AML with spliceosome mutations of SF3B1 or U2AF1. Emavusertib is formulated as tablets for twice daily oral administration. Each treatment cycle will be 28 days in length and repeated in the absence of toxicity. Patients who tolerate emavusertib may continue to receive emavusertib until progression of disease, intolerable toxicity, lack of clinical benefit, withdrawal from the trial, or study termination. The emavusertib starting dose level will be 200 mg twice daily (BID) which was determined to be safe, capable of achieving relevant levels of drug exposure as well as demonstrating signs of biologic activity and clinical efficacy in an ongoing study (Study CA-4948-101). For phase 1, emavusertib is taken daily for 28 days of a 28 day cycle. For Phase 1b, emavusertib is taken daily for 21 days of a 28 day cycle in combination with venetoclax. Venetoclax will be administered at 100 mg orally (Day 1) per the product label at the same time each day with a ramp up over 3 days to 400 mg for 21 days of the 28-day Cycle. Second and subsequent cycles start with the target dose level. In each of the Phase 1/1b cohorts, three patients with AML or MDS were enrolled at the designated dose. If none of the first 3 patients experience a DLT during the first cycle, patients may be enrolled into the next higher dose level. If 1 patient out of the first 3 experiences a DLT, the dose level may be expanded with an additional 3 patients. If 2 or 3 patients out of the first six experienced a DLT, this will be considered a DLT rate above the MTD (> 33%), and additional enrollment will proceed at a lower dose level. Any adverse reaction that lead to dose reduction or discontinuation is considered a DLT unless the adverse reaction is clearly and solely related to disease. The RP2D will be determined by the Clinical Safety Committee (CSC) in consultation with the Sponsor, considering all aspects of safety, tolerability, biologic activity, pharmacokinetics and preliminary efficacy in the trial population. The intent of the RP2D is to provide a dose and schedule that will maximize the opportunity for clinical benefit, while minimizing the risk of toxicity. The RP2D may be below the MTD. The CSC may request enrollment of additional patients at any previously-explored dose level in order to make an appropriate RP2D or MTD determination. The expansion phase will begin once the RP2D from Phase 1 Dose Escalation phase has been identified. There will be 3 Cohorts and patients will be assigned to each Cohort based on baseline disease: R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor; R/R AML with spliceosome mutations of SF3B1 or U2AF1; and R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1 All patients have had ≤ 2 lines of prior systemic anticancer treatment.

Official Title
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A Phase 1/2A, Open Label Dose Escalation and Expansion Study of Orally Administered CA-4948 as a Monotherapy in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Conditions
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Acute Myelogenous Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: Emavusertib
* Drug: Venetoclax
* Drug: Emavusertib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females ≥18 years of age Life expectancy of at least 3 months Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1 Cytomorphology based confirmed diagnosis of MDS or AML (as per WHO 2016 classification) with the following characteristics. Phase 1 Dose Escalation (Monotherapy) • AML (primary or secondary, including treatment-related) after failing at least 1 standard treatment (may include chemotherapy, re induction therapy or stem cell transplantation). OR • Higher-risk R/R MDS that are considered resistant/refractory following at least 2 to 3 cycles of hypermethylating agent (HMA) or evidence of early progression Phase 2a Dose Expansion (Monotherapy) Patients with: R/R AMLwith FLT3 mutations who have been previously treated with a FLT3 inhibitor R/R AML with spliceosome mutations of SF3B1 or U2AF1 R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1 Number of pretreatments: 1 or 2 Acceptable organ function at screening Ability to swallow and retain oral medications Negative serum pregnancy test in women of childbearing potential Women of childbearing potential and men who partner with a woman of childbearing potential must agree to use highly effective contraceptive methods for the duration of the study and for 90 days after the last dose of emavusertib Willing and able to provide written informed consent and comply with the requirements of the trial Able to undergo serial bone marrow sampling and peripheral blood sampling Exclusion Criteria: Diagnosed with acute promyelocytic leukemia (APL, M3) Has known active central nervous system (CNS) leukemia Allogeneic hematopoietic stem cell transplant (Allo-HSCT) within 60 days of the first dose of emavusertib, or clinically significant graft-versus-host disease (GVHD) requiring ongoing up titration of immunosuppressive medications prior to start of emavusertib Chronic myeloid leukemia (CML) Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 3 weeks (or 5 half-lives) prior to start of emavusertib. Localized radiation or surgical resection of skin cancers allowed. Use of any investigational agent within 3 weeks or 5 half-lives, whichever is shorter, prior to start of emavusertib Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy, with the exception of alopecia that has not resolved to Grade ≤ 1within 7 days prior to start of emavusertib; presence of any acute or chronic non-hematological toxicity ≥ Grade 3 at Screening, or prior to start of emavusertib must resolve to ≤ Grade 2. Known allergy or hypersensitivity to any component of the formulation of emavusertib Major surgery, other than diagnostic surgery, <28 days from the start of emavusertib; minor surgery <14 days from the start of emavusertib Patients with active advanced malignant solid tumors Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness Hepatitis B virus (HBV) DNA positive or Hepatitis C virus (HCV) infection <6 months prior to start of emavusertib unless viral load is undetectable, or HCV with cirrhosis Uncontrolled or severe cardiovascular diseaseincluding myocardial infarction or unstable angina within 6 months prior to CA-4948, New York Heart Association Class II or greater congestive heart failure, or left ventricular ejection fraction < 40% by echocardiogram or multi-gated acquisition scan, serious arrhythmias uncontrolled on treatment, clinically significant pericardial disease, cardiac amyloidosis, congenital long QT syndrome, or QTc with Fridericia's correction (QTcF) that is unmeasurable or > 450 msec on Screening electrocardiogram (ECG) Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of emavusertib Pregnant or lactating Systemic fungal, bacterial, viral, or other infection that is not controlled Any other severe, acute, or chronic medical, psychiatric or social condition, or laboratory abnormality that may increase the risk of trial participation or emavusertib administration

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
Interventional Model Description: Phase 1 and 1b follow a 3 + 3 design where 3 patients will be enrolled at the starting dose level. If none of the first 3 patients experience a Dose Limiting Toxicity (DLT) during the 1st cycle, patients may be enrolled into the next higher dose level. If 1 patient out of the first 3 experiences a DLT, the dose level may be expanded with an additional 3 patients. If 2 or 3 patients out of the first sixz experience a DLT, this will be considered a DLT rate above the max tolerated dose (> 33%), and additional enrollment will proceed at a lower dose level. The Phase 2a Dose Expansion will be enrolled after the RP2D is determined from Phase 1. It will be in 3 Cohorts of patients: (1) R/R AML with FTLT-3 mutation who have been previously treated with a FLT3 inhibitor; (2) R/R AML with spliceosome mutations of SF3B1 or U2AF1; and (3) R/R hrMDS (IPSS-R >3.5) with spliceosome mutations of SF3B1 or U2AF1; AND all patients have ≤ 2 lines of prior systemic anti-cancer therapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Emavusertib (CA-4948) dose escalation<br>Patients receive emavusertib monotherapy BID daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Emavusertib<br>* Emavusertib is formulated as a tablet for oral administration for BID dosing in consecutive 28-day cycles. Emavusertib is a novel small molecule inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). IRAK4 kinase plays an essential role in toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways and these pathways are frequently dysregulated in non-Hodgkin's lymphoma and AML/MDS malignancies.<br>* Other names: CA-4948;|
| Experimental: Emavusertib dose escalation + Venetoclax<br>The starting dose for emavusertib will be 200 mg BID for 21 days of a 28-day Cycle. Anticipated emavusertib doses will be 200 and 300 mg BID. Venetoclax will be administered at 100 mg orally (Day 1) per the product label at the same time each day with a ramp up over 3 days to 400 mg for 21days of a 28-day Cycle. Second and subsequent cycles start with target dose level. This arm of the study has been closed to enrollment. | Drug: Venetoclax<br>* Ventoclax is B-cell lymphoma-2 (BCL-2) inhibitor. Venetoclax will be administered at 100 mg orally (Day 1) per the product label at the same time each day with a ramp up over 3 days to 400 mg for 21days of a 28-day Cycle. Second and subsequent cycles start with target dose level.<br>Drug: Emavusertib<br>* Emavusertib is formulated as a tablet for oral administration for BID dosing for 21 days (Days 1-21) of a 28-day Cycle.<br>* Other names: CA-4948;|
| Experimental: Emavusertib monotherapy dose expansion<br>The Expansion phase will begin once the RP2D from Phase 1 Dose Escalation phase has been identified. There will be 3 Cohorts and patients will be assigned to each Cohort based on baseline disease. | Drug: Emavusertib<br>* Emavusertib is formulated as a tablet for oral administration for BID dosing in consecutive 28-day cycles. Emavusertib is a novel small molecule inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). IRAK4 kinase plays an essential role in toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways and these pathways are frequently dysregulated in non-Hodgkin's lymphoma and AML/MDS malignancies.<br>* Other names: CA-4948;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Maximum Tolerated Dose (MTD) of emavusertib (CA-4948) monotherapy (Phase 1) | The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients. | 28 days | 
| Determine the Recommended Phase 2 Dose (RP2D) of emavusertib monotherapy (Phase 1) | The RP2D will be determined by the Clinical Safety Committee (CSC) in consultation with the Sponsor, considering all aspects of safety, tolerability, biologic activity, pharmacokinetics and preliminary efficacy in the trial population. The intent of an RP2D is to provide a dose and schedule that will maximize the opportunity for clinical benefit, while minimizing the risk of toxicity. | 24 months | 
| Determine Maximum Tolerated Dose (MTD) of emavusertib in combination with venetoclax (Phase 1b) | The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients. | 28 days | 
| Determine the Recommended Phase 2 Dose (RP2D) of emavusertib in combination with venetoclax (Phase 1b) | The RP2D will be determined by the Clinical Safety Committee (CSC) in consultation with the Sponsor, considering all aspects of safety, tolerability, biologic activity, pharmacokinetics and preliminary efficacy in the trial population. The intent of an RP2D is to provide a dose and schedule that will maximize the opportunity for clinical benefit, while minimizing the risk of toxicity. | 24 months | 
| To assess anti-cancer activity (Phase 2a - AML patients) | Proportion of patients who achieve CR + CRh | 24 months | 
| To assess anti-cancer activity (Phase 2a - hrMDS patients) | Overall response rate: proportion of patients who achieve CR+PR | 24 months | 
| To assess safety (Phase 1b) | Clinical safety assessments including frequency of adverse events (AEs) | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmax (Phase 1 and 1b) | maximum plasma concentration (Cmax) | 24 months | 
| To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmin (Phase 1 and Phase 1b) | trough plasma concentration (Cmin) | 24 months | 
| To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Tmax (Phase 1 and 1b) | Time to maximum plasma concentration | 24 months | 
| To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Area under the plasma concentration versus time curve(AUC) [0-24] (Phase 1 and 1b) | Area under the plasma concentration-time curve from 0 to 24 hours | 24 months | 
| To characterize the pharmacokinetic (PK) parameters of emavusertib measured by AUC[INF] (Phase 1 and 1b) | Area under the plasma concentration-time curve from 0 to infinity | 24 months | 
| To characterize the pharmacokinetic (PK) parameters of emavusertib measured by T 1/2 (Phase 1 and 1b) | Plasma terminal elimination half-life (T 1/2) | 24 months | 
| To assess clinical response (Phase 1 and 1b) | For AML: assessed by proportion of patients who reach complete response (CR) + complete response with partial hematological recovery (CRh) assessed by proportion of patients who reach complete response with incomplete hematologic recovery (CRi) or CR or Crh For hrMDS: overall response rate of CR+partial response (PR) | 24 months | 
| To assess clinical response (Phase 1 and 1b) | Assessed by transfusion independence | 24 months | 
| To assess tolerability and long term safety (Phase 2a) | Clinical safety assessments including frequency of adverse events (AEs) | 24 months | 
| To assess clinical response (Phase 2a) | For AML - assessed by proportion of patients who achieve CR or CRh or CRi; For hrMDS - assessed by proportion of patients who achieve CR or PR or mCR | 24 months | 
| To assess clinical response (Phase 2a) | Assessed by duration of response (DOR) | 24 months | 
| To assess clinical response (Phase 2a) | Assessed by time to response | 24 months | 
| To assess clinical response (Phase 2a) | Assessed by transfusion independence | 24 months | 
| To assess clinical response (Phase 2a) | Assessed by overall survival (OS) | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myelogenous Leukemia, Myelodysplastic Syndrome, AML, MDS, IRAK4, FLT3-ITD mutant, FLT3 Wild Type (WT), resistant/refractory to HMA, spliceosome mutation, SF3B1, U2AF1, SRSF2, ZRSR2, high risk AML, high risk MDS, resistant/refractory to r/r to HMA, failing prior treatment