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
For WM/LPL
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.
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.
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.
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).
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).
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.
Blast transformation of CML into AML.