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

Sponsor

Curis, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT04278768

Collaborator

(none)

178

Enrollment

Locations

Arms

68.8

Anticipated Duration (Months)

19.8

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief 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, FLT3-ITD mutant AML patients after failing at least 1 to 3 pretreatments, including a FLT3 inhibitor
R/R AML with FLT3 WT, after failing 1 to 3 pretreatments. Desired enrichment for expression of spliceosome mutations
R/R hrMDS with spliceosome mutations (SF3B1, U2AF1, SRSF2, ZRSR2), resistant/refractory to HMA; ineligible for intensive chemotherapy; maximal 3 pretreatments
R/R hrMDS without spliceosome mutations; resistant/refractory to r/r to HMA; ineligible for intensive chemotherapy; maximal 3 pretreatments

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia Myelodysplastic Syndrome	Drug: Emavusertib Drug: Azacitidine Drug: Venetoclax Drug: Emavusertib	Phase 1/Phase 2

Detailed 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 AML or 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, that are VEN naïve, 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 FLT3-Wildtype (WT) and R/R hrMDS 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 collaboration 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 4 Cohorts and patients will be assigned to each Cohort based on baseline disease:

Cohort 1: R/R AML, FLT3-ITD mutant AML patients after failing at least 1 to 3 pretreatments, including a FLT3 inhibitor
Cohort 2: R/R AML with FLT3 WT, after failing 1 to 3 pretreatments. Desired enrichment for expression of spliceosome mutations
Cohort 3: R/R hrMDS with spliceosome mutations (SF3B1, U2AF1, SRSF2, ZRSR2), resistant/refractory to HMA; ineligible for intensive chemotherapy; maximal 3 pretreatments
Cohort 4: R/R hrMDS without spliceosome mutations; resistant/refractory to r/r to HMA; ineligible for intensive chemotherapy; maximal 3 pretreatments

Study Design

Study Type:

Interventional

Anticipated Enrollment :

178 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention 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 siz 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. In Phase 2a Dose Expansion (Monotherapy), for each Cohort a Simon-2-Stage design will be employed with a minimum of 9 patients enrolled in each cohort (Stage 1). If a response is observed, a total of 30 patients will be enrolled in each Cohort. If the clinical response rate is ≥ 30% in any Cohort, additional patients (max of 35) may be entered to provide a tighter estimate of the 95% confidence interval around the clinical response rate.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 siz 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. In Phase 2a Dose Expansion (Monotherapy), for each Cohort a Simon-2-Stage design will be employed with a minimum of 9 patients enrolled in each cohort (Stage 1). If a response is observed, a total of 30 patients will be enrolled in each Cohort. If the clinical response rate is ≥ 30% in any Cohort, additional patients (max of 35) may be entered to provide a tighter estimate of the 95% confidence interval around the clinical response rate.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

TakeAim Leukemia: 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 and in Combination With Azacitidine or Venetoclax

Actual Study Start Date :

Jul 6, 2020

Anticipated Primary Completion Date :

Apr 1, 2026

Anticipated Study Completion Date :

Apr 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Emavusertib (CA-4948) dose escalation Patients receive emavusertib monotherapy PO BID daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Emavusertib 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. Other Names: CA-4948
Experimental: Emavusertib dose escalation + Azacitidine The starting dose level for emavusertib will be 200 mg BID for 21 days (Days 1-21) of a 28-day Cycle. Anticipated emavusertib doses will be 200, 300, 400 mg BID. Azacitidine 75 mg/m2 intravenous (IV) or subcutaneously (SC) will be administered as 7 doses on a 28-day Cycle (e.g., 7 consecutive doses or split doses with weekend break 5-2, starting at Day 1)	Drug: Azacitidine Azacitidine is a chemotherapy drug. Azacitidine 75 mg/m2 intravenous (IV) or subcutaneously (SC) will be administered as 7 doses on a 28-day Cycle. Drug: Emavusertib Emavusertib is formulated as a tablet for oral administration for BID dosing for 21 days (Days 1-21) of a 28-day Cycle.
Experimental: Emavusertib dose escalation + Venetoclax The starting dose level for emavusertib will be 200 mg BID for 21 days of a 28-day Cycle. Anticipated emavusertib doses will 200, 300, 400 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.	Drug: Venetoclax 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. Drug: Emavusertib Emavusertib is formulated as a tablet for oral administration for BID dosing for 21 days (Days 1-21) of a 28-day Cycle.
Experimental: Emavusertib monotherapy dose expansion The Expansion phase will begin once the RP2D from Phase 1 Dose Escalation phase has been identified. There will be 4 Cohorts and patients will be assigned to each Cohort based on baseline disease.	Drug: Emavusertib 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. Other Names: CA-4948

Outcome Measures

Primary Outcome Measures

Determine Maximum Tolerated Dose (MTD) of emavusertib (CA-4948) monotherapy (Phase 1) [28 days]
The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients.
Determine the Recommended Phase 2 Dose (RP2D) of emavusertib monotherapy (Phase 1) [24 months]
The RP2D will be determined by the Clinical Safety Committee (CSC) in collaboration 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.
Determine Maximum Tolerated Dose (MTD) of emavusertib in combination with azacitidine (Phase 1b) [28 days]
The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients.
Determine the Recommended Phase 2 Dose (RP2D) of emavusertib in combination with azacitidine (Phase 1b) [24 months]
The RP2D will be determined by the Clinical Safety Committee (CSC) in collaboration 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.
Determine Maximum Tolerated Dose (MTD) of emavusertib in combination with venetoclax (Phase 1b) [28 days]
The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients.
Determine the Recommended Phase 2 Dose (RP2D) of emavusertib in combination with venetoclax (Phase 1b) [24 months]
The RP2D will be determined by the Clinical Safety Committee (CSC) in collaboration 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.
To assess complete response (Phase 2a) [24 months]
Clinical response: A Simon 2-stage design will be followed to determine if further evaluation is needed.
To assess duration of response (Phase 2a) [24 months]
Clinical response: A Simon 2-stage design will be followed to determine if further evaluation is needed.
To assess safety (Phase 2a) [24 months]
Clinical safety assessments including frequency of adverse events (AEs)

Secondary Outcome Measures

To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmax (Phase 1 and 1b) [24 months]
maximum plasma concentration (Cmax)
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmin (Phase 1 and Phase 1b) [24 months]
trough plasma concentration (Cmin)
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Tmax (Phase 1 and 1b) [24 months]
Time to maximum plasma concentration
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) [24 months]
area under the plasma concentration-time curve from 0 to 24 hours
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by AUC[INF] (Phase 1 and 1b) [12 months]
area under the plasma concentration-time curve from 0 to infinity
To characterize the pharmacokinetic (PK) parameters of emavusertib measured by T 1/2 (Phase 1 and 1b) [24 months]
Plasma terminal elimination half-life (T 1/2)
To assess overall response rate (ORR) (Phase 1 and 1b) [24 months]
Assessed by clinical response

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Males and females ≥18 years of age
Life expectancy of at least 3 months
Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤2
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).

• 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)
HMA and ventoclax naïve, and ineligible for intensive chemotherapy

Doublet Arm: emavusertib + Venetoclax

Patients with:

R/R AML or hrMDS, after first line therapy
Venetoclax naïve

Phase 2a Dose Expansion (Monotherapy)

Patients with:

R/R AML, FLT3-ITD mutant AML patients after failing at least 1 and maximal 3 pretreatments, including a FLT3 inhibitor FLT3 inhibitor
R/R AML with FLT3 WT, after failing 1 to 3 pretreatments. Desired enrichment for expression of spliceosome mutations (SF3B1, U2AF1, SRSF2, ZRSR1)
R/R hrMDS with spliceosome mutations of SF3B1 and U2AF1 only resistant/refractory to HMA; ineligible for intensive chemotherapy. maximal 3 pretreatments
R/R hrMDS without SF3B1 or U2AF1spliceosome mutations (can have SRSF2 or ZRSR2 mutations); resistant/refractory to r/r to HMA; ineligible for intensive chemotherapy, maximal 3 pretreatments

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 days from the start of 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 female
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Moffitt Cancer Center	Tampa	Florida	United States	33612
2	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
3	Oncology Hematology West, PC dba Nebraska Cancer Specialists	Omaha	Nebraska	United States	68130
4	Albert Einstein Medical College	Bronx	New York	United States	10461
5	Novant Health Hematology - Forsyth	Winston-Salem	North Carolina	United States	27103
6	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
7	Marien Hospital Dusseldorf; Klinik fur Onkologie und Hamatologie, Palliativmedizin	Düsseldorf		Germany	40479
8	Universitatsklinikum Leipzig; Medizinische Klinik und Poliklinik I	Leipzig		Germany	04103
9	Klinikum rechts der Isar der Technischen Universitat Munchen	München		Germany	81675