Non Hodgkin Lymphoma Clinical Trial
Dose Escalation/ Expansion Study of CA-4948 as Monotherapy in Patients With AML or MDS
Summary
This is a multicenter, open-label, Phase 1/2a dose escalation and expansion study of orally administered emavusertib (CA-4948) monotherapy and in combination with azacitidine or venetoclax in adult patients with Acute Myelogenous Leukemia (AML) or high risk Myelodysplastic Syndrome (MDS).
R/R AML with FLT3 mutations, R/R including a FLT3 inhibitor
R/R AML with sliceosome mutations of SF3B1 or U2AF1
R/R hrMDS with spliceosome mutations of SF3B1 or U2AF1; bone marrow blast count >/= 8%; ineligible for intensive chemotherapy
Number of pretreatments: 1 or 2
Full Description
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.
Eligibility Criteria
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
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There are 25 Locations for this study
Tampa Florida, 33612, United States
Atlanta Georgia, 30322, United States
Chicago Illinois, 60611, United States
Chicago Illinois, 60637, United States
Boston Massachusetts, 02215, United States
Omaha Nebraska, 68130, United States
Bronx New York, 10461, United States
Rochester New York, 14642, United States
Winston-Salem North Carolina, 27103, United States
Columbus Ohio, 43210, United States
Houston Texas, 77030, United States
Praha 2 , 12 80, Czechia
Nice , 6200, France
Paris , 75012, France
Paris , 75475, France
Düsseldorf , 40479, Germany
Leipzig , 04103, Germany
München , 81675, Germany
Münster , 48149, Germany
Be'er Sheva , 84100, Israel
H̱olon , 58220, Israel
Jerusalem , 91120, Israel
Cuneo , , Italy
Meldola , , Italy
Gdańsk , 80-21, Poland
Kraków , 31 50, Poland
Barcelona , , Spain
Madrid , 28006, Spain
Madrid , , Spain
Sevilla , , Spain
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