Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 1 for:    4948-102
Previous Study | Return to List | Next Study

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04278768
Recruitment Status : Recruiting
First Posted : February 20, 2020
Last Update Posted : July 9, 2021
Sponsor:
Information provided by (Responsible Party):
Curis, Inc.

Brief Summary:

This is a multicenter, open-label, Phase 1/2a dose escalation and expansion study of orally administered 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: CA-4948 Drug: Azacitidine Drug: Venetoclax Phase 1 Phase 2

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated 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.
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 and in Combination With Azacitidine or Venetoclax
Actual Study Start Date : July 6, 2020
Estimated Primary Completion Date : February 1, 2022
Estimated Study Completion Date : February 1, 2022


Arm Intervention/treatment
Experimental: CA-4948 dose escalation
Patients receive CA-4948 monotherapy 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.

Experimental: CA-4948 dose escalation + Azacitidine
The starting dose level for CA-4948 will be 200 mg BID for 21 days (Days 1-21) of a 28-day Cycle. Anticipated CA-4948 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: CA-4948
CA-4948 is formulated as a tablet for oral administration for BID dosing for 21 days (Days 1-21) of a 28-day Cycle.

Experimental: CA-4948 dose escalation + Venetoclax
The starting dose level for CA-4948 will be 200 mg BID for 21days of a 28-day Cycle. Anticipated CA-4948 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: CA-4948
CA-4948 is formulated as a tablet for oral administration for BID dosing for 21 days (Days 1-21) of a 28-day Cycle.

Experimental: CA-4948 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: 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.




Primary Outcome Measures :
  1. Determine Maximum Tolerated Dose (MTD) of 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.

  2. Determine the Recommended Phase 2 Dose (RP2D) of CA-4948 monotherapy (Phase 1) [ Time Frame: 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.

  3. Determine Maximum Tolerated Dose (MTD) of CA-4948 in combination with azacitidine (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.

  4. Determine the Recommended Phase 2 Dose (RP2D) of CA-4948 in combination with azacitidine (Phase 1b) [ Time Frame: 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.

  5. Determine Maximum Tolerated Dose (MTD) of CA-4948 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.

  6. Determine the Recommended Phase 2 Dose (RP2D) of CA-4948 in combination with venetoclax (Phase 1b) [ Time Frame: 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.

  7. To assess complete response (Phase 2a) [ Time Frame: 24 months ]
    Clinical response: A Simon 2-stage design will be followed to determine if further evaluation is needed.

  8. To assess duration of response (Phase 2a) [ Time Frame: 24 months ]
    Clinical response: A Simon 2-stage design will be followed to determine if further evaluation is needed.

  9. To assess safety (Phase 2a) [ Time Frame: 24 months ]
    Clinical safety assessments including frequency of adverse events (AEs)


Secondary Outcome Measures :
  1. To characterize the pharmacokinetic (PK) parameters of CA-4948 measured by Cmax (Phase 1 and 1b) [ Time Frame: 24 months ]
    maximum plasma concentration (Cmax)

  2. To characterize the pharmacokinetic (PK) parameters of CA-4948 measured by Cmin (Phase 1 and Phase 1b) [ Time Frame: 24 months ]
    trough plasma concentration (Cmin)

  3. To characterize the pharmacokinetic (PK) parameters of CA-4948 measured by Tmax (Phase 1 and 1b) [ Time Frame: 24 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] (Phase 1 and 1b) [ Time Frame: 24 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] (Phase 1 and 1b) [ 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 (Phase 1 and 1b) [ Time Frame: 24 months ]
    Plasma terminal elimination half-life (T 1/2)

  7. To assess overall response rate (ORR) (Phase 1 and 1b) [ Time Frame: 24 months ]
    Assessed by clinical response



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
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. 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: CA-4948 + 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: CA-4948 + 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
  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 90 days 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. 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 within 7 days prior to start of CA-4948
  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 hypersensitivity to azacitidine or mannitol, as stated per label (Phase 1b only)
  11. Patients with active advanced malignant solid tumors
  12. Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness
  13. 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
  14. Uncontrolled or severe cardiovascular disease
  15. Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of CA-4948
  16. 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
  17. Pregnant or lactating female
  18. Systemic fungal, bacterial, viral, or other infection that is not controlled
  19. Any other severe, acute, or chronic medical, psychiatric or social condition, or laboratory abnormality that may increase the risk of trial participation or CA-4948 administration

Information from the National Library of Medicine

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


Contacts
Layout table for location contacts
Contact: Reinhard von Roemeling, MD 617-503-6500 clinicaltrials@curis.com

Locations
Layout table for location information
United States, Florida
Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Principal Investigator: Chetasi Talati, MD         
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.
Layout table for additonal information
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: July 9, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
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
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
Additional relevant MeSH terms:
Layout table for 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
Azacitidine
Venetoclax
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors