An Open-Label, Dose Escalation and Dose Expansion Trial Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered CA-4948 in Patients with Relapsed or Refractory Primary Central Nervous System Lymphoma
- Conditions
- Part A2. Relapsed or Refractory Hematologic Malignancy. (Enrollment is closed)Part B. Primary central nervous system lymphoma (PCNSL)MedDRA version: 21.1Level: LLTClassification code 10066481Term: Hematological malignancySystem Organ Class: 100000004864MedDRA version: 21.0Level: LLTClassification code 10036685Term: Primary central nervous system lymphomaSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2022-000891-20-PL
- Lead Sponsor
- Curis, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 80
- Part A2
1. Males and females >= 18 years of age
2. Life expectancy of at least 3 months
3. ECOG Performance Status of = 1
4. 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 NOS (not otherwise specified-type), and primary or secondary central nervous system CNS lymphoma. 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 or MZL should meet clinical criteria for requiring treatment of their disease.
5. 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.
a. 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 stable disease. NOTE: For confirmation of documented relapse during prior treatment, biopsy/FNA of the lymphoma at Screening is recommended but not mandatory.
b.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.
6.Measurable disease:
Defined as CT scan showing at least 1 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
7.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
8.Acceptable marrow and organ function at screening as described below:
a. ANC = 1,000/µL*
b. Platelet count = 50,000/µL without transfusion within 1 week prior to start of study treatment*
c. 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
d. 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 Sponsor Medical Monitor
9. Ability to swallow and retain oral medications
10. Negative serum pregnancy test in WOCP
11. 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.
12. Willing and able to provide written informed consent and comply with the requirements of the trial
13. CPK < Grade 2
14. Patients on a cholesterol lowering statin must be on a stable dose with no changes within 3 weeks prior to study start
- Part B. Check protocol for complete list.
1. Males and females >= 18 years of age
2. Life expectancy of at least 3 months
3. ECOG Performance Status of =0, 1, or 2
4. Histopathologically confirmed diagnosis of PCNSL (medical record is acceptable). Cerebral biopsies are not required if
All exclusion criteria are detailed in protocol
Part B
1.Patients with only intraocular PCNSL without brain lesion or CSF involvement or T-cell lymphoma or systemic presence of lymphoma, or non-CNS lymphoma metastatic to the CNS
2. Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the
cervix or breast) or prior history of systemic lymphoma, unless the patient has been free of the disease for = 3 years.
3. Active malignancy other than PCNSL requiring systemic therapy
4. History of Grade = 3 rhabdomyolysis without complete recovery
5. Patient has received external beam radiation therapy to the CNS within 28 days prior to Cycle 1 Day 1.
6. Prior investigational drugs (including treatment in clinical research, unapproved combination products, and new dosage forms) within 28 days or 5 half-lives, whichever is shorter, prior to Cycle 1 Day 1; allogeneic hematopoietic stem cell transplant (HSCT) within 60 days prior to C1D1; or clinically significant graft-versus-host disease (GVHD) requiring ongoing up titration of immunosuppressive medications prior to Screening
Note: The use of a stable or tapering dose of immunosuppressive therapy post-HSCT and/or topical steroids for ongoing skin GVHD is permitted with Sponsor Medical Monitor approval
7.Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 14 days prior to Cycle 1 Day 1 (with the exception of ibrutinib for Parts A2 and B, which may be continued as part of this study without interruption)
8.Receiving the following medications within 7 days prior to Cycle 1 Day
1:
a. Medications which, in the opinion of the Investigator, have a high risk of causing prolonged QTc and/or Torsades de Pointes (Appendix L) b.Peg-filgrastim or equivalent
c. St John's Wort
9.History of stroke or intracranial hemorrhage within 6 months prior to Cycle 1 Day 1. Patients with post-biopsy hemorrhagic sequela defined as a small hyperdense lesion < 3 mm on T2 sequence will not be excluded.
10.Patients who require anticoagulation with warfarin or equivalent vitamin K antagonists, including dual antiplatelet agents, within 5 half-lives of the anti-coagulant or 14 days, whichever is longer, prior to Cycle 1 Day 1. Patients who require the use of antiplatelet agents should be discussed with the Sponsor Medical Monitor.
11.Vaccinated with live-attenuated vaccines within 4 weeks prior to Cycle 1 Day 1
12.Concomitant systemic corticosteroid on an ongoing basis within 14 days prior to Cycle 1 Day 1, with the exception of the following:
a.Equivalent of up to 10 mg/day of prednisone for a disease other than PCNSL
b.Equivalent of up to 50 mg/day of prednisone (equal to 8 mg/day of dexamethasone) for patients with lesions of the brain or spinal cord or both
13.Requires treatment with strong cytochrome P450 (CYP3A4) inhibitors or has received a strong CYP3A4 inducer or P-glycoprotein inducer
within 7 days prior to Cycle 1 Day 1
14.Prior history of hypersensitivity or anaphylaxis to CA-4948 or ibrutinib or any excipients
15.Prior history of Stevens Johnson syndrome or toxic epidermal necrolysis
16.Patient who is intolerant of contrast-enhanced MRI due to allergic reactions to contrast agents
17.Major surgery, other than diagnostic surgery, < 28 days prior to Cycle 1 Day 1; minor surgery < 7 days prior to Cycle 1 Day 1
Note: Insertion of a vascular access device is not considered minor
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method