| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced/Metastatic malignancies |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer that is considered to be advanced and may have spread from the primary tumour site to other sites in the body. |
|
| 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 | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 evaluate the investigator-assessed Objective Response Rate (ORR) of Nivolumab monotherapy in advanced or metastatic malignancies of multiple types of cancer |
|
| E.2.2 | Secondary objectives of the trial |
- To assess duration of investigator-assessed clinical response (duration of response)
- To assess time to response (TTR)
- To assess clinical benefit rate (CBR)
- To assess overall survival (OS) at one year
- To assess safety of nivolumab in malignancies in this study
- To correlate clinical response and OS to programmed death-ligand 1 (PD-L1) expression
- To correlate clinical response and OS to MisMatch Repair (MMR) alterations
Exploratory objective:
- To characterize the pharmacokinetics (PK) and immunogenicity of nivolumab monotherapy across malignancies evaluated in this trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Cohorts are comprised of tumor types which may include the following advanced or metastatic malignancies:
1. Adenocarcinoma of the small bowel
2. Adrenocortical carcinoma
3. adenoid cystic carcinoma
4. anal cancer
5. biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma gallbladder cancer, ampullary carcinoma)
6. carcinoid after somatostatin analogs (SSA) (Ki67 less than 20%)
7. cervix cancer (exocervix, squamous cell pathology)
8. endometrial cancer (after primary treatment that includes radiation therapy. Subjects with tumors greater than 10% estrogen receptor positive pathology in the primary tumor are excluded)
9. histiocytoses (including Erdheim Chester disease, Langerhans cell histiocytosis)
10. insulinoma
11. Lynch syndrome associated cancers (excluding hereditary nonpolyposis colorectal cancer [HNPCC]).
12. medullary thyroid cancer
13. Merkel cell carcinoma (includes unresectable disease)
14. nasopharyngeal carcinoma
15. neuroendocrine tumors (poorly differentiated, Ki67 greater than 20%)
16. neuroendocrine tumors (well to moderately differentiated, Ki67 less than 20%)
17. non-lung small cell carcinoma (including small cell carcinoma of the ovary of pulmonary type or small cell ovarian cancer hypercalcemic type)
18. non squamous cell cancer of the head and neck (including cancer of the salivary gland)
19. penile cancer
20. rare women's cancers (high grade, clear cell: greater than 50% clear cell by pathology)
21. soft-tissue sarcoma (including liposarcoma, leiomyosarcoma)
22. malignant peripheral nerve sheath tumor-NF-1
23. testicular cancer (chemotherapy resistant or recurrent within 2 years of primary therapy)
24. thymic carcinoma or invasive thymoma
25. thyroid cancer (anaplastic thyroid cancer as primary therapy)
26. thyroid cancer (papillary or follicular, after failing radioactive iodine [RAI] and after approved kinase inhibition [lenvatinib])
27. uterine sarcoma (excluding endometrial stroma sarcoma)
28. vaginal cancer (squamous cell pathology)
29. vulvar cancer (squamous cell pathology)
2) Adults ≥ 18 years of age
3) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
4) Pathology report confirming diagnosis of malignancy. Subjects will have advanced or metastatic disease. In the case of anaplastic thyroid cancer, subjects may receive nivolumab as part of primary therapy.
5) Subjects must have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors (RECIST)
6) Subjects must have received standard-of-care primary treatment for malignancy and standard-of-care for relapse or refractory disease, if treatment exists. For de novo metastatic disease subjects with recurrent or refractory disease after standard-of-care (first-line therapy or second-line [if treatment exists]) will be eligible for this trial. If there is no standard-of-care treatment for de novo metastatic disease (eg, metastatic carcinoid), subjects are eligible to enroll without prior first-line (or second-line) therapy.
7) Mandatory tissue and blood collection for PD-L1 testing and MMR-deficiency testing. Tumor tissue (formalinfixed, paraffin embedded archival [< 3 months old] or recent acquisition) must be received by a central laboratory before first treatment. In order to receive treatment, the sample must meet the minimum quality requirements, as determined by the central laboratory. If the archival tissue is > 3 months old, a fresh biopsy will be required to obtain sufficient tissue sample for PD-L1 testing. Archival tissue samples are acceptable for MMR
testing. A blood sample must be obtained before the first dose of nivolumab. Test results are not required for enrollment. (Note: Fine Needle Aspiration [FNA] and bone metastases samples are not acceptable for submission.) |
|
| E.4 | Principal exclusion criteria |
1) Subjects who require ongoing treatment with more than 10 mg of prednisone (or steroid equivalent, excluding inhaled or topical steroids) daily
2) Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibodies (including ipilimumab or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways).
3) Subjects with the following malignancies are excluded:
1. adenocarcinoma of the colon
2. adenocarcinoma of the prostate
3. adenocarcinoma of the rectum
4. meningioma (low grade)
5. peritoneal carcinoma
6. primary CNS lymphoma
7. squamous cell carcinoma of the head and neck
8. squamous cell carcinoma of the skin
9. carcinoma of unknown primary
4) Subjects with an active, known, or suspected autoimmune disease (Subjects may enroll with type I diabetes mellitus, hypothyroidism [only requiring hormone replacement], vitiligo, psoriasis, or alopecia not requiring systemic treatment.)
5) Subjects with previous malignancies (except non-melanoma skin cancers, and in situ cancers) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of this trial is investigator-assessed ORR in all treated subjects.
ORR is defined as the number of participants with a best overall response of confirmed CR or PR divided by the number of all treated participants. Best overall response is defined as the best
response designation, as determined by investigator, recorded between the date of first dose and the date of objectively documented progression per tumor-specific response criteria or the date of subsequent therapy, whichever occurs first. For participants without documented progression or subsequent therapy, all available response designations will contribute to the BOR determination. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint is best overall response rate, which is not associated with a particular time.
Response will be assessed at planned response assessments. It is anticipated that for subjects that respond to therapy, a response will be seen at either the Week 16 or Week 28 response assessment.
For simulations, the time to primary endpoint is assumed to be 16 weeks. |
|
| E.5.2 | Secondary end point(s) |
- Duration of the response (DOR)
- Time to Response (TTR)
- Clinical Benefit Rate (CBR)
- Overall Survival (OS) at one year
- Safety and Tolerability
Exploratory Endpoint:
- Characterization of pharmacokinetics (PK) and immunogenicity of nivolumab monotherapy in malignancies evaluated in this trial |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- DOR is defined as the time from first confirmed response (CR or PR) to the date of the first documented tumor progression as determined by investigator or death due to any cause, whichever
occurs first.
- TTR is defined as the time from first dosing date to the date of the first confirmed response, as assessed by investigator.
- CBR is defined as the number of participants with a best overall response of confirmed CR or PR, or stable disease divided by the number of all treated subjects.
- OS is defined as the time from the first dosing date of to the date of death.
- Safety and tolerability will be measured by the incidence of
deaths, AEs, SAEs, AEs leading to discontinuation, immune-mediated AEs, select AEs, AEs leading to dose delay, and specific laboratory abnormalities ...
|
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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) | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
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