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:

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

Inclusion Criteria for Part A1 – Monotherapy Dose Escalation:

  • Males and females ≥ 18 years of age.
  • Life expectancy of at least 3 months.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1.
  • Diagnosis of histopathologically confirmed B-cell hematologic malignancy, as per the World Health Organization (WHO) 2016 classification (Swerdlow et al. 2016); eligible NHL subtypes include follicular lymphoma, MZL, DLBCL, MCL, and WM/LPL without the urgent need for treatment of hyperviscosity.
  • 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 CR, PR, or SD. 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 prior treatment or failure to achieve an objective response on prior treatment.
    • NOTE: Biopsy (preferred) or FNA at Screening is recommended but not mandatory. For WM/LPL:
      • Relapsed is defined per the consensus panel recommendations from the Sixth International Workshop on WM as reappearance of monoclonal immunoglobulin (Ig)M 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 et al. 2009)). For CLL/SLL:
      • Relapsed is defined as evidence of disease. progression in a patient who has previously achieved the above criteria of a CR or PR for ≥ 6 months. Disease progression is defined per iwCLL (Hallek et al. 2018) as:
      • Appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 cm), splenomegaly, hepatomegaly, or other organ infiltrates. Transient increases of lymph node size during treatment with novel inhibitors may occur and should not be counted as PD;
      • An increase by ≥ 50% in greatest determined diameter of any previous site (≥ 1.5 cm).
  • Refractory disease is defined as treatment failure (non-CR/non-PR) or as progression within 6 months from the last dose of therapy.
  • 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 IgM paraprotein with a minimum IgM level of > 2 × ULN;
    • For CLL/SLL: At least 1 criterion for measurable disease per iwCLL (Hallek et al. 2018).
  • Must have recovered from toxicity after any prior autologous stem cell transplants or chimeric antigen receptor (CAR)-T cell therapy, and must have disease progression prior to initiation of study treatment.
  • Acceptable marrow and organ function at screening as described below:
    • Absolute neutrophil count (ANC) ≥ 1,000/µL*;
    • Platelet count ≥ 50,000/µL without transfusion within 1 week prior to start of CA-4948*;
    • Serum creatinine ≤ 1.5 × ULN or a calculated creatinine clearance ≥ 30 mL/min according to Cockcroft-Gault formula (using actual body weight) or by 24-hour urine collection;
    • AST or ALT ≤ 2 × ULN e. 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 (WOCP).
  • WOCP and men who partner with a WOCP must agree to use highly effective contraceptive methods for the duration of the study and for 3 months after the last dose of CA-4948.
  • Willing and able to provide written informed consent and comply with the requirements of the trial.
  • Inclusion criterion 13 was deleted as of protocol v5.0 (retained here to preserve numbering). 

Inclusion Criteria for Part A2 – Combination Therapy Dose Escalation:

  • . Males and females ≥ 18 years of age.
  • Life expectancy of at least 3 months.
  • ECOG Performance Status of ≤ 1.
  • Diagnosis of histopathologically confirmed B-cell NHL, as per the WHO 2016 classification (Swerdlow et al. 2016). Eligible NHL subtypes include follicular lymphoma, MZL, MCL, DLBCL (including extranodal lymphomas of leg-, testicular-, or not otherwise specified [NOS]-type), CLL/SLL, primary or secondary CNS lymphoma and WM/LPL.
    • 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 MCL, MZL, WM/LPL, or CLL/SLL should meet clinical criteria for requiring treatment of their disease.
  • 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. Patients with CLL/SLL must have failed at least 2 prior systemic therapies.
  • For NHL:
    • Relapsed NHL is per Revised Response Criteria for Malignant Lymphoma and as documented by excisional/incisional biopsy (preferred) or FNA or CNB as PD after a CR, PR, or SD. NOTE: For confirmation of documented relapse during prior treatment, biopsy/FNA of the lymphoma at Screening is recommended but not mandatory;
    • Refractory NHL is defined for all eligible NHL by PD (per Revised Response Criteria for Malignant Lymphoma) during prior treatment or failure to achieve an objective response on prior treatment.
    • NOTE: Biopsy (preferred) or FNA at Screening is recommended but not mandatory.
    • For CLL/SLL:
      • Relapsed is defined as evidence of disease progression in a patient who has previously achieved the above criteria of a CR or PR for ≥ 6 months. Disease progression is defined as:
      • Appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 cm), splenomegaly, hepatomegaly, or other organ infiltrates. Transient increases of lymph node size during treatment with novel inhibitors may occur and should not be counted as PD;
      • An increase by ≥ 50% in greatest determined diameter of any previous site (≥ 1.5 cm);
      • Refractory disease is defined as treatment failure (non-CR/non-PR) or as progression within 6 months from the last dose of therapy.
  • Measurable disease (as defined below): For NHL: Defined as 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 CLL/SLL: At least 1 criterion for measurable disease per iwCLL (Hallek et al. 2018).
  • Must have recovered from toxicity after any prior autologous stem cell transplants or CAR-T cell therapy, and must have disease progression prior to initiation of study treatment
  • Acceptable marrow and organ function at screening as described below:
    • ANC ≥ 1,000/µL*;
    • Platelet count ≥ 50,000/µL without transfusion within 1 week prior to start of study treatment*;
    • Serum creatinine ≤ 1.5 × ULN or a calculated creatinine clearance ≥ 30 mL/min according to Cockcroft-Gault formula (using actual body weight) or by 24-hour urine collection;
    • AST or ALT ≤ 2 × ULN e. 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 WOCP.
  • WOCP and men who partner with a WOCP must agree to use highly effective contraceptive methods for the duration of the study and for 3 months after the last dose of study treatment.
  • Willing and able to provide written informed consent and comply with the requirements of the trial.

Inclusion Criteria for Part B – Dose Expansion of Combination Therapy:

  • Males and females ≥ 18 years of age.
  • Life expectancy of at least 3 months.
  • ECOG Performance Status of ≤ 1.
  • Diagnosis of histopathologically confirmed B-cell NHL, including applicable confirmation as per the WHO 2016 classification (Swerdlow et al. 2016):
    • Cohort 1: MZL;
    • Cohort 2: Activated B-cell-like (ABC)-DLBCL, or extranodal subtypes: Leg-, testicular-, or NOS-type. The population will be enriched for MYD88 L265P mutations. As this occurs more frequently in the ABC-DLBCL subtype (Hans et al. 2004), all patients with this subtype qualify for enrollment. If the MYD88 mutation status is unknown at baseline, the lymphoma will be tested for MYD88 mutations. • Cohort 3: PCNSL only. If the MYD88 mutation status is unknown at baseline, the lymphoma will be tested for MYD88 mutations.
    • ohort 4: Patients receiving ibrutinib monotherapy who have developed adaptive, secondary resistance. Indications include:
    • MCL, MZL, CLL/SLL, or WM/LPL.
    • Indications for which ibrutinib is NCCN listed (e.g., PCNSL).
    • Patients with NHL and known myddosome mutations.
    • Patients may be candidates for maintaining ibrutinib while CA-4948 will be added for resistance reversal. A brief gap of ibrutinib therapy of ≤ 3 weeks is acceptable.
  • PCNSL: Failure of at least 1 prior systemic treatment or had inadequate response or intolerance to high-dose methotrexate; DLBCL: failure of 2 prior systemic therapies and naïve to ibrutinib and other Bruton tyrosine kinase inhibitors (Cohorts 1-3) or have developed adaptive, secondary resistance to ibrutinib (Cohort 4). Patients with CLL/SLL must have failed at least 2 prior systemic therapies.
  • Relapsed or refractory disease (as defined below):
    • Relapsed is per Revised Response Criteria for Malignant Lymphoma and as documented by excisional/incisional biopsy (preferred) or FNA or CNB as PD after a CR, PR, or SD. SD should have lasted for ≥ 3 months. Adaptive, secondary resistance: documented progression on ibrutinib after prior response to ibrutinib.
    • 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 prior treatment or failure to achieve an objective response on prior treatment.
    • NOTE: Biopsy (preferred) or FNA at Screening is recommended but not mandatory.
  • Measurable disease by CT and/or positronic emission tomography (PET)-CT. PET-CT is required at baseline and for confirmation of CR.
  • Must have recovered from toxicity after any prior autologous stem cell transplants or CAR-T cell therapy, and must have disease progression prior to initiation of study treatment
  • Acceptable marrow and organ function at screening as described below:
    • ANC ≥ 1,000/µL*;
    • Platelet count ≥ 50,000/µL without transfusion within 1 week prior to start of study treatment*;
    • Serum creatinine ≤ 1.5 × ULN or a calculated creatinine clearance ≥ 30 mL/min according to Cockcroft-Gault formula (using actual body weight) or by 24-hour urine collection;
    • AST or 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 WOCP.
    • WOCP and men who partner with a WOCP must agree to use highly effective contraceptive methods for the duration of the study and for 3 months after the last dose of study treatment.
    • Willing and able to provide written informed consent and comply with the requirements of the trial.
    • 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.

Exclusion Criteria:

  • Patients with active CNS involvement other than PCNSL at study entry are ineligible. Patients with prior CNS disease (leptomeningeal disease or brain metastasis) that has been adequately treated (e.g., radiation or intravenous or intrathecal chemotherapy) are permitted, but must have completed such treatment and have no evidence of active CNS disease for at least 4 weeks prior to the first dose of study treatment. Intrathecal chemoprophylaxis to prevent the emergence or recurrence of lymphoma in the CNS is permitted on study during dose expansion only and may be administered per institutional guidelines.
  • Radiotherapy delivered to non-target lesions involving > 25% of bone marrow within 1 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).
  • Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc, received within 14 days prior to start of study treatment (with the exception of ibrutinib for Parts A2 and B, which may be continued as part of this study without interruption).
  • 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 study treatment;
    • Inhaled, intranasal, intra-articular, and topical steroids are permitted.
  • Use of any investigational agent within 21 days or 5 half-lives, whichever is shorter, prior to start of study treatment.
  • 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, as determined by NCI CTCAE v4.03, within 7 days prior to start of study treatment unless approved by the Medical Monitor.
  • Known allergy or hypersensitivity to any component of the formulation of CA-4948 (or ibrutinib for entry into Parts A2 or B) used in this study.
  • Major surgery, other than diagnostic surgery, < 28 days from the start of study treatment; minor surgery < 14 days from the start of study treatment.
    • NOTE: Insertion of a vascular access device is not considered minor surgery.
  • Known to be human immunodeficiency virus 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 study treatment unless viral load is undetectable, or HCV with cirrhosis.
    • NOTE: testing required only in patients with history of HBV or history of HCV < 6 months prior to start of study treatment).
    • In patients with a history of HBV, hepatitis B core antibody testing is required and if positive, then hepatitis B 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 the start of study treatment; New York Heart Association Class II or greater congestive heart failure; serious arrhythmias requiring medication for treatment; clinically significant pericardial disease; cardiac amyloidosis; or QTc with Fridericia’s correction (QTcF) that is unmeasurable or ≥ 480 msec on Screening ECG. NOTE: For QTcF ≥ 480 msec on the Screening ECG, the ECG may be repeated twice at least 24 hours apart; the mean QTcF from the 3 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 study treatment. 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 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 study treatment, 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 non-melanoma skin cancer, carcinoma in situ [including superficial bladder cancer and cervical intraepithelial neoplasia], and organconfined 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 study treatment administration, may interfere with the informed consent process and/or with compliance with the requirements of the trial, 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.
  • B-cell NHL of the following subtypes:
    • Burkitt lymphoma;
    • Lymphoblastic lymphoma or leukemia;
    • Post-transplantation lymphoproliferative disorder;
    • Known primary mediastinal, ocular, or epidural DLBCL.
  • WM patients requiring urgent treatment due to hyperviscosity.

Eligibility last updated 4/14/22. Questions regarding updates should be directed to the study team contact.

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.

Contact us for the latest status

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Allison Rosenthal, D.O.

Contact us for the latest status

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Jacksonville, Fla.

Mayo Clinic principal investigator

Han Tun, M.D.

Contact us for the latest status

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

Publications are currently not available
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CLS-20403518

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