| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Part A2. Relapsed or Refractory Hematologic Malignancy. (Enrollment is closed)
Part B. Primary central nervous system lymphoma (PCNSL) |
|
| E.1.1.1 | Medical condition in easily understood language |
Part A2. Relapsed or Refractory Hematologic Malignancy. (Enrollment is closed)
Part B. Primary central nervous system lymphoma (PCNSL) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066481 |
| E.1.2 | Term | Hematological malignancy |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036685 |
| E.1.2 | Term | Primary central nervous system lymphoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- Part A (Dose Escalation Phase):
To determine the safety and tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of oral CA-4948 as monotherapy and in combination with ibrutinib
- Part B (PCNSL Expansion Phase)
Safety of CA-4948 in combination with ibrutinib in patients with PCNSL |
|
| E.2.2 | Secondary objectives of the trial |
•Part A2: Dose escalation of CA-4948 in combination with ibrutinib. To assess:
- the pharmacokinetic (PK) profile of CA-4948 and ibrutinib
- overall response rate (ORR) following treatment
- duration of response (DOR) following treatment
- disease control rate (DCR) following treatment
- progression-free survival (PFS) following treatment
-overall survival (OS) following treatment
•Part B: PCNSL expansion cohorts of CA-4948 in combination with ibrutinib.
- To evaluate anti-cancer activity of CA-4948 in combination with ibrutinib in patients with PCNS
- To further assess anti-cancer activity of CA-4948 in combination with ibrutinib
- To assess PK profile of CA-4948 in combination with ibrutinib
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- 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 imaging reveals typical
images of PCNSL
a.Patients with parenchymal lesions must have unequivocal evidence (eg, presence of at least 1 bi-dimensionally measurable target lesion on
brain magnetic resonance imaging (MRI) or head CT or a new lesion with CSF involvement) of disease progression on imaging within 28 days prior to Cycle 1 Day 1.
b.For patients with leptomeningeal disease only, CSF cytology must document lymphoma cells or monotypic cells on flowcytometry, and/or
imaging findings consistent with CSF disease within 28 days prior to Cycle 1 Day 1 (at the discretion of the Investigator).
5. Relapsed or refractory to a systemic frontline chemotherapy (eg, high-dose methotrexate-based therapies) AND no more than a total of 3 lines of prior anti-PCNSL therapies (patients with 4 prior lines of therapy may be allowed after consultation with the Sponsor Medical Monitor) AND the following:
a.For Cohort 1, prior exposure to a Bruton tyrosine kinase (BTK) inhibitor alone or in combination is acceptable.
b. For Cohort 2, must have direct progression on a BTK inhibitor (administered as monotherapy or in combination).
6. Patients must be able to tolerate gadolinium-enhanced MRI or contrast-enhanced CT
7. Patients must be able to tolerate lumbar punctures.
9.CPK elevation < 2.5× ULN |
|
| E.4 | Principal exclusion criteria |
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 surgery.
18.Viral infections:
a. Known to be HIV positive or have an acquired immunodeficiency syndrome-related illness. If HIV is undetectable or maintained on treatment, enrollment may be allowed after discussion with the Sponsor b. HBV DNA positive or HCV infection < 6 months prior to Cycle 1 Day 1 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 Cycle 1 Day 1.
c. Active systemic infection, including a HIV, cytomegalovirus infection or SARS-CoV-2, or has had, within 28 days prior to Cycle 1 Day 1, an infection (other than nail trichophytosis) that requires hospitalization or an intravenous antibiotic
19.Concomitant illness that would preclude safe participation in study, including:
a.Uncontrolled or severe cardiovascular disease, including myocardial infarction or unstable angina within 6 months prior to Cycle 1 Day 1, New York Heart Association Class II or greater congestive heart failure or left ventricular ejection fraction < 40% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan, serious arrhythmias uncontrolled on treatment, clinically significant pericardial disease, cardiac myloidosis, or QTcF that is unmeasurable or > 450 msec on Screening electrocardiogram (ECG) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A (Dose Escalation Phase):
-Incidence of DLTs
-Incidence of adverse events (AEs)
-Clinically significant changes in vital signs and laboratory parameters
-Clinically significant changes from baseline in electrocardiograms (ECGs)
Part B PCNSL:
Incidence of AEs including serious adverse events (SAEs), ECGs, laboratory values, vital signs, and physical examinations
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: First 21 days after first dose
Part B: there is no defined patient duration period.
For both Parts: Permitted to continue until the point of disease progression, intolerable toxicity or withdrawal of consent |
|
| E.5.2 | Secondary end point(s) |
Parts A1 and A2 (Dose Escalation Phase):
- Maximum observed plasma concentration (Cmax)
- Minimum observed plasma concentration (Cmin)
-Time after dosing that a drug is present at the maximum concentration in serum (Tmax)
-Area under the concentration-time curve (AUC)
-Terminal elimination half-life (T1/2)
-ORR: complete response (CR) + partial response (PR)
-Waldenström macroglobulinemia/ lymphoplasmacytic lymphoma (WM/LPL) ORR: CR + PR + very good partial response (VGPR)
-DOR: time from CR or PR to first documentation of relapse, disease progression, or death from any cause
-WM/LPL DOR: time from CR, PR, or VGPR + Stable disease
-DCR: PR + CR + stable disease (SD)
-WM/LPL DCR: CR + PR + VGPR + SD
-PFS: time from date of first dose of study treatment until first documentation of relapse, disease progression, or death from any cause
-OS: time from date of first dose of study treatment until death from any cause
Part B (PCNSL) Cohorts:
- Incidence of AEs including serious adverse events (SAEs), ECGs, laboratory values, vital signs, and physical examinations
-ORR: proportion of patients achieving CR + unconfirmed complete response (CRu) + PR
-DCR:proportion of patients achieving CR + CRu + PR + CR + stable disease
-Progression-free survival (PFS)
-Overall survival (OS)
- PK parameters including maximum observed plasma concentration (Cmax) and area under the concentration curve (AUC) of: CA-4948 ibrutinib |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A: First 21 days after first dose
Part B: there is no defined patient duration period.
For both Parts: Permitted to continue until the point of disease progression, intolerable toxicity or withdrawal of consent |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Part A1 and A2 are closed |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Israel |
| United States |
| Czechia |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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