Dose Escalation/ Expansion Study of CA-4948 as Monotherapy in Patients With AML or MDS
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ClinicalTrials.gov Identifier: NCT04278768 |
Recruitment Status :
Recruiting
First Posted : February 20, 2020
Last Update Posted : March 12, 2024
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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.
Condition or disease | Intervention/treatment | Phase |
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Acute Myelogenous Leukemia Myelodysplastic Syndrome | Drug: Emavusertib Drug: Venetoclax | Phase 1 Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 366 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 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) |
Primary Purpose: | Treatment |
Official Title: | 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 |
Actual Study Start Date : | July 6, 2020 |
Estimated Primary Completion Date : | April 1, 2026 |
Estimated Study Completion Date : | April 1, 2026 |
Arm | Intervention/treatment |
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Experimental: Emavusertib (CA-4948) dose escalation
Patients receive emavusertib monotherapy BID daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
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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 Name: CA-4948 |
Experimental: Emavusertib dose escalation + Venetoclax
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
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.
Other Name: CA-4948 |
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 3 Cohorts and patients will be assigned to each Cohort based on baseline disease.
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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 Name: CA-4948 |
- Determine Maximum Tolerated Dose (MTD) of emavusertib (CA-4948) monotherapy (Phase 1) [ Time Frame: 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) [ Time Frame: 24 months ]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.
- Determine Maximum Tolerated Dose (MTD) of emavusertib in combination with venetoclax (Phase 1b) [ Time Frame: 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) [ Time Frame: 24 months ]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.
- To assess anti-cancer activity (Phase 2a - AML patients) [ Time Frame: 24 months ]Proportion of patients who achieve CR + CRh
- To assess anti-cancer activity (Phase 2a - hrMDS patients) [ Time Frame: 24 months ]Overall response rate: proportion of patients who achieve CR+PR
- To assess safety (Phase 1b) [ Time Frame: 24 months ]Clinical safety assessments including frequency of adverse events (AEs)
- To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmax (Phase 1 and 1b) [ Time Frame: 24 months ]maximum plasma concentration (Cmax)
- To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmin (Phase 1 and Phase 1b) [ Time Frame: 24 months ]trough plasma concentration (Cmin)
- To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Tmax (Phase 1 and 1b) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 24 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) [ Time Frame: 24 months ]Plasma terminal elimination half-life (T 1/2)
- To assess clinical response (Phase 1 and 1b) [ Time Frame: 24 months ]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)
- To assess clinical response (Phase 1 and 1b) [ Time Frame: 24 months ]Assessed by transfusion independence
- To assess tolerability and long term safety (Phase 2a) [ Time Frame: 24 months ]Clinical safety assessments including frequency of adverse events (AEs)
- To assess clinical response (Phase 2a) [ Time Frame: 24 months ]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
- To assess clinical response (Phase 2a) [ Time Frame: 24 months ]Assessed by duration of response (DOR)
- To assess clinical response (Phase 2a) [ Time Frame: 24 months ]Assessed by time to response
- To assess clinical response (Phase 2a) [ Time Frame: 24 months ]Assessed by transfusion independence
- To assess clinical response (Phase 2a) [ Time Frame: 24 months ]Assessed by overall survival (OS)
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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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
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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)
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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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04278768
Contact: Reinhard von Roemeling, MD | 617-503-6500 | clinicaltrials@curis.com |
Responsible Party: | Curis, Inc. |
ClinicalTrials.gov Identifier: | NCT04278768 |
Other Study ID Numbers: |
CA-4948-102 |
First Posted: | February 20, 2020 Key Record Dates |
Last Update Posted: | March 12, 2024 |
Last Verified: | March 2024 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
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 |
Leukemia Preleukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Myelodysplastic Syndromes Syndrome Disease Pathologic Processes |
Neoplasms by Histologic Type Neoplasms Hematologic Diseases Bone Marrow Diseases Precancerous Conditions Venetoclax Antineoplastic Agents |