Non Hodgkin Lymphoma Clinical Trial

Dose Escalation/ Expansion Trial of CA-4948 as Monotherapy and in Combination With Azacitidine or Venetoclax 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

View Full Description

Full Description

The primary objective of Phase 1 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 Phase 1b 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.

The primary objective of Phase 2a of the study (emavusertib monotherapy expansion) is to assess complete response (CR) and duration of response in patients with R/R FLT-3 AML, R/R AML with sliceosome mutations of SF3B1 or U2AF1 and R/R hrMDS with sliceosome mutations of SF3B1 or U2AF1 and to assess tolerability, and long-term safety.

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, 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.

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 the target dose level.

Azacitidine 75 mg/m2 intravenous (IV) or subcutaneously (SC) will be administered as 7 doses on a 28 Cycle (e.g., 7 consecutive doses or split doses with weekend break 5-2), starting at Day 1, and in accordance with local prescribing information.

In each of the Phase 1/1b cohorts, three patients with AML or MDS will be 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 experience 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 leads 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 AMLwith FLT3 mutations, R/R including a FLT3 inhibitor
R/R AML with spliceosome 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

View Eligibility Criteria

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 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

• High-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 1b (Combination Therapy) Doublet Arm: emavusertib + AZA

Patients:

with International Prognostic Scoring System- revised (IPSS- R) High, high risk myelodysplastic syndrome (hrMDS)
ineligible for intensive chemotherapy

Doublet Arm: emavusertib + Venetoclax

Patients with:

• R/R AML or hrMDS, after first line therapy

Phase 2a Dose Expansion (Monotherapy)

Patients with:

R/R AMLwith FLT3 mutations, R/R including a FLT3 inhibitor
R/R AML with spliceosome 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
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 14 days prior to start of emavusertib. Localized radiation or surgical resection of skin cancers allowed.
Use of any investigational agent within 28 days 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 ≤1 within 7 days prior to start of emavusertib
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 emavusertib
Known hypersensitivity to azacitidine or mannitol, as stated per label (Phase 1b only)
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 disease
Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of emavusertib
History of other invasive malignancy, unless definitively treated with curative intent, provided it is deemed to be at low risk for recurrence by the treating physician
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

Study is for people with:

Non Hodgkin Lymphoma

Phase:

Phase 1

Estimated Enrollment:

325

Study ID:

NCT04278768

Recruitment Status:

Recruiting

Sponsor:

Curis, Inc.

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There are 9 Locations for this study

See Locations Near You

Moffitt Cancer Center
Tampa Florida, 33612, United States
Dana Farber Cancer Institute
Boston Massachusetts, 02215, United States
Oncology Hematology West, PC dba Nebraska Cancer Specialists
Omaha Nebraska, 68130, United States More Info
Stefano Tarantolo, MD
Principal Investigator
Albert Einstein Medical College
Bronx New York, 10461, United States
Novant Health Hematology - Forsyth
Winston-Salem North Carolina, 27103, United States More Info
James P Dugan, MD
Principal Investigator
The University of Texas MD Anderson Cancer Center
Houston Texas, 77030, United States
Marien Hospital Dusseldorf; Klinik fur Onkologie und Hamatologie, Palliativmedizin
Düsseldorf , 40479, Germany
Universitatsklinikum Leipzig; Medizinische Klinik und Poliklinik I
Leipzig , 04103, Germany
Klinikum rechts der Isar der Technischen Universitat Munchen
München , 81675, Germany

How clear is this clinincal trial information?

Study is for people with:

Non Hodgkin Lymphoma

Phase:

Phase 1

Estimated Enrollment:

325

Study ID:

NCT04278768

Recruitment Status:

Recruiting

Sponsor:


Curis, Inc.

How clear is this clinincal trial information?

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