A Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered CA-4948 in Patients with Relapsed or Refractory Hematologic Malignancies

Overview

About this study

This is a multi-center, open-label trial of orally administered CA-4948 monotherapy in adult patients with Relapsed or Refractory NHL. The trial will be conducted in 2 parts: an initial Dose Escalation Phase (Part A) of CA-4948 in patients with Relapsed or Refractory Non-Hodgkin Lymphoma, (RR NHL) and a Dose Expansion Phase (Part B) of CA-4948 in patients with RR NHL with and without myeloid differentiation primary response 88 (MYD88) mutations. During Part B, patients will be enrolled regardless of MYD88 mutation status.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

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 ≤ 1.

For NHL

  • Confirmed B-cell NHL (as per the World Health Organization [WHO] 2016 classification; (Swerdlow_2016) including WM/LPL with the following exceptions:
    • High-grade B-cell lymphoma, not otherwise specified (NOS)
    • Burkitt lymphoma
    • Lymphoblastic lymphoma or leukemia
    • Chronic lymphocytic leukemia and small lymphocytic lymphoma
    • Post-transplantation lymphoproliferative disorder
    • Known primary mediastinal, ocular, epidural, testicular or breast DLBCL
    • WM patients requiring urgent treatment due to hyperviscosity
      • NOTE: Once a dose has been shown not to exceed the MTD in NHL patients, other hematological malignancies can be considered for enrollment in specific malignancies that have been approved by the CSC and Sponsor. Patients with WM, mantle cell lymphoma, or marginal zone lymphoma should meet clinical criteria for requiring treatment of their disease. In dose expansion, the following histologies are permitted:
        • DLBCL, NOS, High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements, WM/LPL, marginal zone lymphoma, and mantle cell lymphoma.

For AML

  • Diagnosis of histopathologically confirmed AML (as per the World Health Organization [WHO] 2016 classification; Owen_2013) that is relapsed and/or refractory and documented to have FLT3 mutation by a prior test.
    • NOTE: The diagnosis and evaluation of AML will be made by bone marrow aspiration and/or biopsy. If an aspirate is unobtainable (i.e., a “dry tap”), the diagnosis may be made from the core biopsy.
  • Relapsed or refractory disease (as defined below) for which patients are ineligible for or have exhausted standard therapeutic options that would be considered standard of care

For NHL other than WM/LPL

  • Relapsed is per Revised Response Criteria for Malignant Lymphoma and as documented by excisional/incisional biopsy (preferred) or fine needle aspiration (FNA) or core needle biopsy (CNB) as PD after a complete response (CR).
    • NOTE: For confirmation of documented relapse during prior treatment, biopsy/FNA of the lymphoma at Screening is recommended but not mandatory.
  • Refractory is defined for all eligible NHL by PD (Per Revised Response Criteria for Malignant Lymphoma) during or after prior treatment. NOTE: Biopsy (preferred) or Fine Needle Aspiration (FNA) at Screening is recommended but not mandatory.

For WM/LPL

  • Relapse is defined per the consensus panel recommendations from the Sixth International Workshop on WM as reappearance of monoclonal IgM protein and/or recurrence of bone marrow involvement, lymphadenopathy/splenomegaly or symptoms attributable to active disease after CR.
  • Refractory is defined by symptomatic disease after prior treatment for WM requiring therapy (according to the consensus panel recommendations from the Fourth International Workshop on WM (Dimopoulos_2009).

For AML

  • Relapsed AML is defined per 2003 Revised IWG for AML as any of the following after attainment of a CR: reappearance of leukemic blasts in peripheral blood; >5% myeloblasts in bone marrow; reappearance or development of extramedullary disease; new dysplastic changes.
  • Refractory AML is defined as failure to achieve a CR after most recent therapy.
    • NOTE: Untreated AML patients who are ≥60 years of age and are not candidates for standard therapy due to age, performance status, and/or adverse risk factors, according to the treating physician may be enrolled upon approval from the Medical Monitor.
  • Measurable disease (as defined below):
  • For NHL other than WM/LPL
    • Computed tomography (CT) scan showing at least 1 or more clearly demarcated lymph node(s) with a long axis > 1.5 cm and short axis > 1.0 cm or 1 clearly demarcated extranodal lesion(s) with a long axis > 1.0 cm and short axis > 1.0 cm. All lesions must have a maximum diameter of < 10 cm.
  • For WM/LPL
    • Presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level of >2 times the upper limit of normal (ULN).
  • If patient has history of prior autologous stem cell transplant, must be > 6 months prior to start of CA-4948.
  • Acceptable marrow and organ function at screening as described below:
    • For NHL only: Absolute neutrophil count (ANC) ≥ 1,000/μL*;
    • For NHL only: Platelet count ≥ 75,000/μL without transfusion within 1 week prior to start of CA-4948*;
    • Serum creatinine ≤ 1.5 × ULN or a calculated creatinine clearance ≥ 50 mL/min according to Cockcroft-Gault formula (using actual body weight) or by 24-hour urine collection;
    • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2 × ULN;
    • Total bilirubin ≤ 1.5 × ULN or ≤3 × ULN in patients with documented Gilbert’s syndrome.
      • *NOTE: For patients with bone marrow involvement of their disease, eligibility will be determined following discussion between Investigator and Medical Monitor.
  • 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 3 months after the lastdose of CA-4948
  • Willing and able to provide written informed consent and comply with the requirements of the trial.
  • Biopsy requirement for NHL:
    • For Part A the Biomarker Sub-Study, only: consent to pre and on treatment tumor biopsies (of lesion with estimated risk of less than 2% for serious complication) for research purposes;
    • For Part B dose expansion: confirmed availability of viable tissue (defined as most recent available archival tumor tissue, or fresh baseline tumor biopsies of lesion with estimated risk of less than 2% for serious complication) for central laboratory testing prior to study dosing.
  • Biopsy requirement for AML: AML patients must be amenable to serial bone marrow sampling and peripheral blood sampling during the study. The diagnosis and evaluation of AML will be made by bone marrow aspiration and/or biopsy. If an aspirate is unobtainable (i.e., a “dry tap”), the diagnosis may be made from the core biopsy.

Exclusion Criteria:

  • Active central nervous system (CNS) involvement of their malignancy.
  • Radiotherapy delivered to non-target lesions within one week prior to starting study treatment or delivered to target lesions that will be followed on the study (NOTE: prior sites of radiation will be recorded).
  • History of allogeneic stem cell transplant.
  • Any prior anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 21 days prior to start of CA-4948.
  • Current or planned glucocorticoid therapy, with the following exceptions:
    • Doses ≤ 10 mg/day prednisolone or equivalent is allowed, provided that the steroid dose has been stable or tapering for at least 14 days prior to the first dose of CA-4948;
    • Inhaled, intranasal, intraarticular and topical steroids are permitted.
  • Use of any investigational agent within 28 days prior to start of CA-4948.
  • 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 unless approved by the Medical Monitor.
  • Known allergy or hypersensitivity to any component of the formulation of CA-4948 used in this study.
  • Major surgery, other than diagnostic surgery, < 28 days from the start of CA-4948; minor surgery < 14 days from the start of CA-4948.
    • NOTE: Insertion of a vascular access device is not considered minor surgery.
  • 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 CA-4948 unless viral load is undetectable, or HCV with cirrhosis (NOTE: testing only required in patients with history of HBV or history of HCV <6 months prior to start of CA-4948).
    • In patients with a history of HBV, hepatitis B core antibody (HBcAb) testing is required and if positive, then HB DNA testing will be performed and if positive the patient will be excluded.
  • Uncontrolled or severe cardiovascular disease, including myocardial infarction, unstable angina, or atrial fibrillation within 6 months prior to CA-4948, New York Heart Association (NYHA) Class II or greater congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, cardiac amyloidosis, or QTc with Fridericia’s (QTcF) correction that is unmeasurable or ≥ 480 msec on Screening electrocardiogram (ECG).
    • NOTE: for QTcF ≥ 480 sec on the Screening ECG, the ECG may be repeated twice at least 24 hours apart; the mean QTcF from the three Screening ECGs must be < 480 msec in order to meet eligibility for trial participation.
  • Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of CA-4948. This includes uncontrolled diarrhea (> 1 watery stool/day), major abdominal surgery, significant bowel obstruction and/or  gastrointestinal diseases that could alter the assessment of PK or safety, including but not limited to: irritable bowel syndrome, ulcerative colitis, Crohn’s disease and hemorrhagic CA-coloproctitis.
  • History of other invasive malignancy, unless adequately treated with curative intent and with no known active disease present within 2 years prior to the start of CA-4948, provided it is deemed to be at low risk for recurrence by the treating physician (NOTE: these latter conditions include but are not limited to nonmelanoma skin cancer, carcinoma in situ [including superficial bladder cancer and cervical intraepithelial neoplasia] and organ-confined prostate cancer).
  • Concomitant use of drugs with a known risk of causing prolonged QTc and/or Torsades de Pointes or a history of risk factors for Torsades de Pointes (e.g., Familial long QT syndrome, heart failure, left ventricular hypertrophy). See crediblemeds.org for a list of drugs that may prolong QT by risk category.
  • Pregnant or lactating female.
  • Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
  • 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, may interfere with the informed consent process and/or may interfere with the interpretation of the trial results and, in the Investigator's opinion, would make the patient inappropriate for entry into this trial.
  • Additional Exclusion Criteria for AML
  • Diagnosed with acute promyelocytic leukemia (APL, M3).
  • Has known active central nervous system (CNS) leukemia; patients with previously treated CNS disease may participate provided they are stable (without evidence of active disease by imaging for at least 4 weeks prior to the first dose of treatment, and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to start of CA-4948.
  • Hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of CA-4948, or immunosuppressive therapy post HSCT at the time of screening, or clinically significant graft-versus-host disease (GVHD) following prior allogeneic transplant with GVHD present within 3 months prior to start of CA-4948.
    • NOTE: The use of a stable dose of oral steroids post HSCT and/or topical steroids for ongoing skin GVHD is permitted with Medical Monitor approval.
  • Blast transformation of CML into AML.

 

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Grzegorz Nowakowski, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Allison Rosenthal, D.O.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Jacksonville, Fla.

Mayo Clinic principal investigator

Han Tun, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

Publications are currently not available

Study Results Summary

Not yet available

Supplemental Study Information

Not yet available

.
CLS-20403518

Mayo Clinic Footer