| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Thymic Carcinoma & B3-thymoma. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Thymic Carcinoma & B3-thymoma |
|
| 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 | PT |
| E.1.2 | Classification code | 10055108 |
| E.1.2 | Term | Thymic cancer metastatic |
| 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 | PT |
| E.1.2 | Classification code | 10043670 |
| E.1.2 | Term | Thymoma |
| 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 assess the efficacy of pembrolizumab and lenvatinib in pre-treated relapsed/recurrent B3-thymoma and Thymic carcinoma (TC) patients in terms of progression free survival (PFS) rate at 5 months. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the efficacy of pembrolizumab and lenvatinib in pre-treated advanced B3-thymoma and TC patients in terms of PFS, response rate (RR), disease control rate (DCR) Duration of response (DoR), tumor shrinkage and overall survival (OS).
• To assess the safety and toxicity profile of the combination according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v.5.0). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Relapsed / Recurrent histologically confirmed B3-Thymoma or TC patients not amenable to curative-intent radical surgery and/or radiotherapy, regardless of PD-L1 expression.
2. Patients progress after at least one previous line of platinum-based chemotherapy for advanced disease:
a. Patients treated with neo-adjuvant or adjuvant platinum-based chemotherapy combined with radical surgery or as part of radical chemo-radiotherapy are eligible if chemotherapy was completed within 6 months before enrolment.
3. Negative result for Myasthenia Gravis (MG) by acetylcholine receptor antibodies test. Presence of acetylcholine receptor antibodies will be considered a positive result for MG, regardless of the value.
4. Male/female who are at least 18 years of age on the day of signing informed consent.
5. ECOG performance status 0-1
6. Life expectancy ≥ 3 months
7. Radiological progression documented per RECIST 1.1 during or after completion of previous line therapy, per investigator’s criteria.
8. Presence of measurable disease according to RECIST 1.1 criteria. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
a. Disease status must be documented by full chest and upper abdomen (including adrenal glands) CT and/or MRI within 28 days prior study enrolment. If clinically indicated, brain imaging must be performed;
9. Provides historical (obtained archived FFPE) or fresh tumor biopsy specimen for biomarker studies, if feasible. Archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated is acceptable. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archival tissue. Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut.
10. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies:
a) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
OR
b) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 6 months after the last dose of study treatment.
11. Adequate bone marrow and organ function according to Table 1 (section 3.1.1).
12. Written informed consent prior to beginning specific protocol procedures. |
|
| E.4 | Principal exclusion criteria |
1. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).
2. Has received prior therapy with sunitinib.
3. Any evidence of active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are clinically stable (i.e. without evidence of progression by imaging for at least four weeks prior to enrolment and any neurologic symptoms have returned to baseline), and have not received steroids (for a total equivalent dose of more than 10 mg of prednisone per day) for at least 7 days prior to enrolment.
4. Presence of acetylcholine receptor antibodies regardless of the value.
5. Uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in spite of an optimized regimen of antihypertensive medication.
6. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at Screening.
7. Intratumor cavitation, direct invasion of main mediastinal blood vessels by the tumor or exist previous bleeding.
8. Fraction ejection < 50%
9. Chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in the last 15 days prior to enrolment:
a. Daily prednisone at doses up to 10 mg or equivalent doses of any other corticosteroid is allowed for example as replacement therapy;
10. History of interstitial lung disease (ILD) OR pneumonitis (other than COPD exacerbation) that has required oral or IV steroids;
11. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed;
12. History of any other hematologic or primary solid tumor malignancy, unless in remission for at least 5 years and without specific treatment (as example, not allowed hormonal therapy to replace for breast cancer or hormonal therapy substitution in prostate cancer). pT1-2 prostatic cancer Gleason score < 6, superficial bladder cancer, non-melanomatous skin cancer or carcinoma in situ of the cervix are allowed;
13. Previous allogenic tissue/solid organ transplantation
14. Active infection requiring systemic therapy.
15. Has received prior radiotherapy within 2 weeks of start of study treatment.
16. Has an intestinal disease not allowing swallowing pills. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Progression free survival (PFS) rate at 5 months, defined as the percentage of patients with B3-Thymoma and TC without disease progression at 5 months after starting the treatment combination. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time from randomization to disease progression |
|
| E.5.2 | Secondary end point(s) |
• Response rate (RR) with the treatment combination
• Maximum tumor shrinkage with the treatment combination
• Disease control rate (DCR) with the treatment combination
• Duration of response (DoR) with the treatment combination
• Overall survival (OS)
• Safety and toxicity profile of the combination according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v.5.0). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Time from randomization to 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | 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 | Yes |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| End of study date, or clinical cut-off, is defined as the Last Patient Last Visit (LPLV) at the end of the follow-up period. This will be the last data collection point, which can be a clinic visit, a sample analysis or a follow-up phone contact. Unless premature termination of the study, end of study date will occur on the last safety follow-up visit after the last dose of study treatment is administered to the last patient in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 32 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 32 |
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