| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Primary Central Nervous System Lymphoma (PCNSL) and Relapsed/Refractory Primary Testicular Lymphoma (PTL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Central Nervous System Cancer and Testicular Cancer |
|
| 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 | 20.0 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10043302 |
| E.1.2 | Term | Testicular cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the clinical benefit of nivolumab in subjects with relapsed/refractory PCNSL or relapsed/refractory PTL as measured by ORR by blinded Independent Central Review (BICR). |
|
| E.2.2 | Secondary objectives of the trial |
-) To assess PFS based on BICR assessment for PCNSL or PTL, respectively
-) To assess ORR and DOR based on investigator assessment for PCNSL or PTL, respectively
-) To assess overall survival (OS) for PCNSL or PTL, respectively |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| This protocol will include both sample collection and residual sample storage for additional research. This collection for additional research is intended to expand the translational research and development capability at BMS, and will support as yet undefined research aims that will advance our understanding of disease and options for treatment. It may also be used to support health authority requests for analysis, and advancement of pharmacodiagnostic development to better target drugs to the right patients. |
|
| E.3 | Principal inclusion criteria |
1. Signed Written Informed Consent
2. Target Population
a) Subject must be 18 years of age or older
b) Subjects with pathologically confirmed PCNSL or PTL who progressed after or did not respond to at least 1 line of systemic therapy
i) PCNSL prior therapy may include HD-MTX, HD-MTX-based regimen, high-dose cytarabine, radiation therapy alone as treatment or as part of consolidation therapy, high-dose therapy with autologous stem cell transplant as part of consolidation therapy, and/or intraocular MTX alone or as part of consolidation therapy
ii) PTL prior therapy may include chemo-immunotherapy (eg, CHOP-R or any other regimens), with/without prophylactic RT to contralateral testis or intrathecal chemotherapy
c) Measurable disease requirements on scans done within 28 days of first dose (14 days for MRI of the brain):
i) PCNSL subjects should have at least 1 measurable extranodal brain lesion with the longest diameter > 1.0 cm on Gd-enhanced MRI
ii) PTL subjects should have at least 1 measurable extranodal lesion with the longest diameter > 1.0 cm on fluorodeoxyglucose (FDG) PET/CT scan (or spiral CT/MRI in patients who cannot undergo FDG PET/CT)
d) Archived tumor block or unstained slides from biopsy. Histologically confirmed tissue will be required from the time of relapse or at the time of initial surgery.
e) Subjects must have a Karnofsky performance status of 70-100 (Appendix 2)
f) Subject re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (ie, subject has not been treated). If re-enrolled, the subject must be re-consented and assigned a new subject number by the IVRS.
g) Subjects with prior history of allogeneic transplant can participate if the transplant was performed at least 6 or more months before screening. If there is no prior history of Grade 2 + acute graft versus host disease (GVHD), no history of extensive or Grade 4 chronic GVHD, or no immunosuppressive therapy for a minimum of 4 weeks with no clinically apparent GVHD.
3. Physical and Laboratory Test Findings
Screening laboratory values must meet the following criteria (using Common Terminology Criteria for Adverse Events [CTCAE] v4.03):
a) Whole blood count (WBC) more or equal to 2000/uL
b) Neutrophils more or equal to 1500/uL
c) Platelets more or equal to 100x103/uL
d) Hemoglobin more or equal to 9.0 g/dL
e) Serum creatinine less or equal to 1.5x upper limit of normal (ULN) or calculated creatinine clearance > 50 mL/min (using the Cockcroft-Gault formula) Female creatinine clearance (CrCl) = (140 - age in years) x weight in kg x 0.85
72 x serum creatinine in mg/dL
Male CrCl = (140- age in years) x weight in kg x 1.00
72 x serum creatinine in mg/ dL
f) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less or equal to 3.0 x ULN
g) Total bilirubin (TBILI) less or equal to 1.5 x ULN (except subjects with Gilbert Syndrome who must have a total bilirubin level of < 3.0xULN)
4. Age and Reproductive Status
a) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of study drug
b) Women must not be pregnant or breastfeeding
c) WOCBP must agree to follow instructions for method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo 5 half-lives (23 weeks). The terminal half-life of nivolumab is up to 25 days.
d) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo five half-lives (31 weeks). The terminal half-life of nivolumab is up to 25 days.
e) Azoospermic males are exempt from contraceptive requirements. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements, but still must undergo pregnancy testing as described in this section. |
|
| E.4 | Principal exclusion criteria |
1. Target Disease Exceptions
a) Intraocular PCNSL without evidence of brain disease
b) PCNSL patients who cannot undergo MRI with contrast assessments
c) PCNSL patients with systemic disease
2. Medical History and Concurrent Diseases
a) Subjects with an active, known, or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
b) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. Dose of dexamethasone less or equal to 4 mg/day or equivalent for PCNSL or PTL with brain and/or spine lesions is allowed.
c) Subjects who have received chemotherapy within 3 weeks of study treatment (except: HD-MTX within 2 weeks of treatment permitted if serum MTX levels < 1 micoM and meets other lab criteria for inclusion), nitrosoureas within 6 weeks of treatment, therapeutic anti-cancer antibodies (such as rituximab) within 4 weeks, radio- or toxin immuneconjugates within 10 weeks of treatment.
d) Received any investigational agent within 28 days or 5 half-lives (whichever is shorter) prior to initiation of study treatment
e) Major surgery and/or radiotherapy within 14 days prior to initiation of study treatment
f) Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally
g) Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
h) Patients with serious or uncontrolled medical disorders
i) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
3. Physical and Laboratory Test Findings
a) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection, and/or detectable virus
4. Allergies and Adverse Drug Reaction
a) History of severe allergy or hypersensitivity to study drug components
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a subject. Strict conditions apply and BMS approval is required.)
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is BICR-assessed ORR. It is defined as the best response designation recorded between the date
of first study drug dose and the date of initial objectively documented progression per criteria or the date of subsequent therapy, whichever occurs first.
The BICR-assessed objective response will be further characterized by the DOR. DOR is defined as the time from first response (partial response [PR] or complete response [CR]) to the date of initial objectively documented progression as determined using the International Primary CNS Lymphoma Collaborative Group (IPCG) criteria for PCNSL and Lugano 2014 response evaluation for PTL, as determined by BICR, or death due to any cause, whichever occurs first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint will be analyzed 6 months after last patient first treatment in each cohort. All treated subjects will be evaluated. |
|
| E.5.2 | Secondary end point(s) |
| The secondary endpoints are PFS based on BICR assessment, ORR and DOR based on investigator assessment, and OS. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Tumor assessments for PCNSL will occur every 2 months for 2 years, then every 6 months until disease progression.
Tumor assessments for PTL will occur every 2 months for 6 months, then every 3 months for 1.5 years, then every 6 months until disease progression. |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Czech Republic |
| France |
| Hong Kong |
| Hungary |
| Israel |
| Italy |
| Russian Federation |
| Singapore |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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