| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-small cell lung cancer, predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, or melanoma (excluding uveal melanoma). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Specific types of lung, kidney, endometrium, bladder, head and neck cancers, as well as melanoma. |
|
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014733 |
| E.1.2 | Term | Endometrial cancer |
| 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 | LLT |
| E.1.2 | Classification code | 10064467 |
| E.1.2 | Term | Urothelial carcinoma |
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067946 |
| E.1.2 | Term | Renal cell carcinoma |
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025650 |
| E.1.2 | Term | Malignant melanoma |
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060121 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck |
| 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 |
| Phase 2 – Expansion In Selected Tumor Types (Expansion): To evaluate objective response rate as of Week 24 (ORR(Week 24): complete response + partial response [CR(Week 24) + PR(Week 24)]) of lenvatinib in combination with pembrolizumab in each of the cohorts using immune-related RECIST (irRECIST). |
|
| E.2.2 | Secondary objectives of the trial |
To assess:
- the tolerability and safety profile of lenvatinib in combination with pembrolizumab
- ORR by irRECIST of lenvatinib in combination with pembrolizumab in subjects with solid tumors
- Progression-free survival (PFS) by irRECIST
- Overall survival (OS)
- Duration of response (DOR) by irRECIST
- Disease control rate (DCR: CR + PR + stable disease [SD]) by irRECIST
- Durable Stable Disease rate (DSDR (SD ≥23 weeks)) by irRECIST
- Clinical benefit rate (CBR: CR, PR + durable SD) by irRECIST
- Pharmacokinetic (PK) profiles of lenvatinib during combination treatment. |
|
| 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 |
TRANSLATIONAL SUB-STUDY
To investigate the relationship between candidate efficacy biomarkers and anti-tumor activity of lenvatinib in combination with pembrolizumab:
a. To evaluate the relationship between PD-L1 expression levels and other relevant biomarkers (eg, tumor infiltrating lymphocytes, T-cell repertoire, ribonucleic acid [RNA] signature profiles) in tumor samples
and anti-tumor activity of lenvatinib in combination with pembrolizumab.
b. To evaluate differences in tumor tissue characteristics in biopsies taken post treatment with lenvatinib in combination with pembrolizumab versus baseline. |
|
| E.3 | Principal inclusion criteria |
1. Phase 2: Histologically and/or cytologically confirmed metastatic selected solid tumor types with 0-2 prior lines of systemic therapy (unless discussed with the sponsor).
As of Amendment 06, for the renal cell carcinoma (RCC) cohort, all subjects must have progressed on treatment with an anti-PD-1/PD-L1 mAb administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies, and as of Amendment 07, the regimen with an anti-PD-1/PD-L1 mAb must be the most recent therapy.
Selected tumor types of both phases: non-small cell lung cancer, predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, or melanoma (excluding uveal melanoma).
2. Life expectancy of 12 weeks or more
3. Phase 2: Measurable disease meeting the following criteria:
- At least 1 lesion of ≥10 mm in the longest diameter for a non-lymph node or ≥15 mm in the short-axis diameter for a lymph node that is serially measurable according to irRECIST using computerized
tomography/magnetic resonance imaging (CT/MRI).
- Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as radiofrequency (RF) ablation must show subsequent evidence of substantial size increase to be deemed a target lesion.
4. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1.
5. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤ 150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to the Cycle 1 Day 1.
6. Adequate renal function defined as creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥40 mL/min per the Cockcroft and Gault formula with creatinine levels >1.5 × ULN.
7. Adequate bone marrow function:
- Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5 × 103/μL)
- Platelets ≥ 100,000/mm3 (≥100 × 109/L)
- Hemoglobin ≥ 9.0 g/dL
8. Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) ≤ 1.5.
9. Adequate liver function as evidenced by bilirubin ≤1.5 times the upper limit of normal (ULN) and alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3×ULN
(in the case of liver metastases ≤5×ULN). In case ALP is >3×ULN (in the absence of liver metastases) or >5×ULN (in the presence of liver metastases) AND the subject also is known to have bone metastases, the
liver specific ALP isoenzyme must be separated from the total and used to assess the liver function instead of the total ALP.
10. Males or females age ≥ 18 years at the time of informed consent.
11. Subjects with known brain metastases will be eligible if they have completed the primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery or complete surgical resection) and if they have remained clinically stable, asymptomatic and off of steroids for at least 28 days before starting study treatment. |
|
| E.4 | Principal exclusion criteria |
1. Prior anticancer treatment within 28 days (or 5 times the half-life, whichever is shorter) or any investigational agent within 30 days prior to the first dose of study drugs. All acute toxicities related to prior treatments must be resolved to Grade ≤1.
2. Subjects must have recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy.
3. Subjects having >1+ proteinuria on urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria. Subjects with urine protein ≥1 g/24-hour will be ineligible.
4. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib
5. New York Heart Association congestive heart failure of grade II or above, unstable angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia associated with significant cardiovascular impairment within the past 6 months
6. Prolongation of QTc interval to >480 msec
7. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug
8. Active infection (any infection requiring systemic treatment)
9. Subject is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B or Hepatitis C
10. Serious nonhealing wound, ulcer, or bone fracture
11. Known intolerance to either of the study drugs (or any of the excipients)
12. History of organ allograft (subject has had an allogenic tissue/solid organ transplant)
13. Biologic response modifiers (eg, granulocyte colony-stimulating factor) within 4 weeks before study entry. Chronic erythropoietin therapy is permitted provided that no dose adjustments were made
within 2 months before first dose of study treatment.
14. Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical study
15. Females who are pregnant or breastfeeding
16. Excluding the primary tumor leading to enrollment in this study, any other active malignancy (except for definitively treated melanoma insitu, basal or squamous cellcarcinoma of the skin, or carcinoma in-situ of the bladder or cervix) within the past 24 months
17. Prior treatment with lenvatinib or any PD-1, anti-PD-L1, or anti-PDL2 agent, excluding the melanoma, NSCLC cohorts, where prior treatment with one PD-1, anti-PD-L1, or anti-PD-L2 agent is allowed.
18. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids (up to 7.5mg/d of prednisone or equivalent) may be approved after consultation with the sponsor.
19. No active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
20. Has a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis
21. Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR(Week 24) is defined as the proportion of subjects who have BOR of irCR(Week 24) or irPR(Week 24) as of the Week 24 tumor assessment time point. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
ORR is defined as the proportion of subjects who have BOR of irCR or irPR at the time of data cutoff.
PFS is defined as the time from the first study dose date to the date of first documentation of confirmed disease progression or death (whichever occurs first).
OS is measured from the start date of the treatment period until date of death from any cause. Subjects who are lost to follow-up and the subjects who are alive at the date of data cutoff will be censored at the
date the subject was last known alive.
DCR is defined as the proportion of subjects who have BOR of irCR or irPR or irSD (minimum duration from C1D1 to irSD ≥5 weeks).
CBR is defined as the proportion of subjects who have BOR of irCR or irPR or durable irSD (duration of irSD ≥23 weeks).
DOR is defined as the duration of irCR or irPR.
Durable SD rate is defined as the proportion of subjects whose BOR is irSD and the duration of irSD ≥23weeks. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR: at the time of data cutoff.
PFS: the date of first documentation of confirmed disease progression or death (whichever occurs first).
OS: date of death from any cause. Subjects who are lost to follow-up and the subjects who are alive at the date of data cutoff will be censored at the date the subject was last known alive.
DCR (minimum duration from C1D1 to irSD ≥5 weeks).
CBR (duration of irSD ≥23 weeks).
DOR is defined as the duration of irCR or irPR.
Durable SD rate: duration of irSD ≥23weeks. |
|
| 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 | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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.8.3 |
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 | 13 |
| 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 |
| Norway |
| Spain |
| Sweden |
| United States |
|
| 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
|
| The definition of the end of the study for each cohort is the time of data cutoff for the final analysis or the time of last subject/last treatment, whichever occurs later. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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