An Open Label Dose Escalation Trial of CA-4948 in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndrome

• ClinicalTrials.gov Identifier: NCT04278768
• Recruitment Status: Recruiting
• First Posted: February 20, 2020
• Last Update Posted: November 20, 2020
• Sponsor: Curis, Inc.
• Information provided by (Responsible Party): Curis, Inc.

Study Description

Brief Summary:

This is a multicenter, open-label, dose escalation Phase 1 study of orally administered CA-4948 monotherapy in adult patients with Acute Myelogenous Leukemia (AML) or high risk Myelodysplastic Syndrome (MDS).

Condition or disease	Intervention/treatment	Phase
Acute Myelogenous Leukemia; Myelodysplastic Syndrome	Drug: CA-4948	Phase 1

Detailed Description:

The primary objective of the study is to determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) for CA-4948 in patients with AML and high risk MDS based on the safety and tolerability, dose-limiting toxicities (DLTs), and Pharmacokinetic (PK)/Pharmacodynamic (PD) findings.

CA-4948 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 CA-4948 may continue to receive CA-4948 until progression of disease, intolerable toxicity, withdrawal from the trial, or study termination.

The 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). 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 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Three patients with AML or MDS will be enrolled at the starting dose level. If none of the first 3 patients experience a Dose Limiting Toxicity (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 maximum tolerated dose (> 33%), and additional enrollment will proceed at a lower dose level.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Open Label Dose Escalation Trial Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered CA-4948 in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndrome
• Actual Study Start Date: July 6, 2020
• Estimated Primary Completion Date: February 1, 2022
• Estimated Study Completion Date: February 1, 2022

Arms and Interventions

Arm

Intervention/treatment

Experimental: CA-4948 dose escalation; Patients receive CA-4948 PO BID daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: CA-4948; CA-4948 is formulated as a tablet for oral administration for BID dosing in consecutive 28-day cycles. CA-4948 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.

Outcome Measures

Primary Outcome Measures :

1. Determine Maximum Tolerated Dose (MTD) [ 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.
2. Determine the Recommended Phase 2 Dose (RP2D) [ Time Frame: 12 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.

Secondary Outcome Measures :

1. To characterize the pharmacokinetic (PK) parameters of CA-4948 measured by Cmax [ Time Frame: 12 months ]
   maximum plasma concentration (Cmax)
2. To characterize the pharmacokinetic (PK) parameters of CA-4948 measured by Cmin [ Time Frame: 12 months ]
   trough plasma concentration (Cmin)
3. To characterize the pharmacokinetic (PK) parameters of CA-4948 measured by Tmax [ Time Frame: 12 months ]
   Time to maximum plasma concentration
4. To characterize the pharmacokinetic (PK) parameters of CA-4948 measured by Area under the plasma concentration versus time curve(AUC) [0-24] [ Time Frame: 12 months ]
   area under the plasma concentration-time curve from 0 to 24 hours
5. To characterize the pharmacokinetic (PK) parameters of CA-4948 measured by AUC[INF] [ Time Frame: 12 months ]
   area under the plasma concentration-time curve from 0 to infinity
6. To characterize the pharmacokinetic (PK) parameters of CA-4948 measured by T 1/2 [ Time Frame: 12 months ]
   Plasma terminal elimination half-life (T 1/2)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

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

4. Patients with:

   1. Relapsed or refractory AML OR
   2. High/very high risk relapsed/refractory MDS, following at least 6 cycles of hypomethylating agents [HMA] or evidence of early progression
5. Acceptable organ function at screening
6. Ability to swallow and retain oral medications
7. Negative serum pregnancy test in women of childbearing potential
8. 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 1 month after the last dose of CA-4948
9. Willing and able to provide written informed consent and comply with the requirements of the trial
10. Able to undergo serial bone marrow sampling and peripheral blood sampling

Exclusion Criteria:

1. Diagnosed with acute promyelocytic leukemia (APL, M3)
2. Has known active central nervous system (CNS) leukemia
3. Allogeneic hematopoietic stem cell transplant (Allo-HSCT) within 60 days of the first dose of CA-4948, or clinically significant graft-versus-host disease (GVHD) requiring ongoing up titration of immunosuppressive medications prior to start of CA-4948
4. Blast phase of chronic myeloid leukemia (CML)
5. Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 14 days prior to start of CA-4948. Localized radiation or surgical resection of skin cancers allowed.
6. Use of any investigational agent within 28 days or 5 half-lives, whichever is shorter, prior to start of CA-4948
7. 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
8. Known allergy or hypersensitivity to any component of the formulation of CA-4948
9. Major surgery, other than diagnostic surgery, <28 days from the start of CA-4948; minor surgery <14 days from the start of CA-4948
10. Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness
11. Hepatitis B virus (HBV) DNA positive or Hepatitis C virus (HCV) infection <6 months prior to start of CA-4948 unless viral load is undetectable, or HCV with cirrhosis
12. Uncontrolled or severe cardiovascular disease
13. Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of CA-4948
14. 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
15. Pregnant or lactating female
16. Systemic fungal, bacterial, viral, or other infection that is not controlled

Contacts and Locations

Contacts

Contact: Reinhard von Roemeling, MD; 617-503-6500; clinicaltrials@curis.com

Locations

United States, Massachusetts

Dana Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02215

Principal Investigator: Eric S Winer, MD

United States, Nebraska

Oncology Hematology West, PC dba Nebraska Cancer Specialists; Recruiting

Omaha, Nebraska, United States, 68130

Principal Investigator: Stefano Tarantolo, MD

United States, New York

Albert Einstein Medical College; Recruiting

Bronx, New York, United States, 10461

Principal Investigator: Amit K Verma, MD

United States, North Carolina

Novant Health Hematology - Forsyth; Recruiting

Winston-Salem, North Carolina, United States, 27103

Principal Investigator: James P Dugan, MD

United States, Texas

The University of Texas MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Principal Investigator: Guillermo Garcia-Manero, MD

Sponsors and Collaborators

Curis, Inc.

More Information

• Responsible Party: Curis, Inc.
• ClinicalTrials.gov Identifier: NCT04278768
• Other Study ID Numbers: CA-4948-102
• First Posted: February 20, 2020
• Last Update Posted: November 20, 2020
• Last Verified: November 2020

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

Keywords provided by Curis, Inc.:

Acute Myelogenous Leukemia; Myelodysplastic Syndrome; AML; MDS; IRAK4

Additional relevant MeSH terms:

Leukemia; Preleukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Syndrome; Disease; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions