Lenvatinib and Pembrolizumab in Resectable Mucosal Melanoma

A Phase II Study of Neoadjuvant Lenvatinib and Pembrolizumab in Resectable Mucosal Melanoma

This study is a randomized ,single center clinical study which is designed to investigate whether combination of Pembrolizumab with Lenvatinib could improve pCR rate and consequent survival in resectable mucosal melanoma.

All the eligible patients were assigned to receive Lenvatinib once a day (QD) for 6 weeks plus pembrolizumab on Day 1 of each 21-day cycle (Q3W) concurrently on days 1 and 22, followed by surgery and 18 cycles of Pembrolizumab 200mg q3w of adjuvant phase.

Study Overview

• Status: Not yet recruiting
• Conditions: Mucosal Melanoma; Neoadjuvant Treatment
• Intervention / Treatment: Drug: Lenvatinib, Pembrolizumab

Detailed Description

Mucosal melanoma is a rare type of melanoma in Caucasian population and a dominate subtype in Asia, which generally carries a worse prognosis than cutaneous melanoma. Surgery remains the primary therapeutic intervention for mucosal melanoma, and neoadjuvant therapy is still needed which can lead to improvements in outcomes by surgical resectability, local control and organ preservation.

Immunotherapy has showed promising activity in advanced melanoma. However, PD-1 antibodies, both Pembrolizumab and Nivolumab, showed much poorer response to mucosal melanoma than to cutaneous melanoma.

Pembrolizumab showed modest objective response rate (ORR, 13%) in advanced mucosal melanoma in Chinese population (NCT02628067). Recent study also demonstrated that neoadjuvant therapy with one dose of Pembrolizumab could lead to pathological complete response (pCR) or major response in nearly 30% of resectable advanced melanoma and pCR was associated with reduced risk of recurrence and improved survival.

Lenvatinib is also a kinase inhibitor that inhibits the kinase activities of VEGFR1,2, 3 which has been approved by FDA for differentiated thyroid cancer, advanced renal cell carcinoma and hepatocellular carcinoma.

It is hypothesized that neoadjuvant Pembrolizumab in combination with Lenvatinib could result in higher anti-tumor activity with lower toxicity and prolong RFS and OS in high-risk resectable mucosal melanoma.

The study will assess the efficacy and safety of the combination Pembrolizumab and Lenvatinib as neoadjuvant treatment in resectable mucosal melanoma.

• Study Type: Interventional
• Enrollment (Anticipated): 26
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jun Guo, MD; Phone Number: 86-10-88196317; Email: guoj307@126.com
• Study Contact Backup: Name: Lu si, MD; Phone Number: 86-10-88196317; Email: silu15_silu@126.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100142
      • Beijing Cancer hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1. Be willing and able to provide written informed consent for the trial. 2. Be a male or female subject and is 18-75 years of age on day of signing informed consent.

  3. Have histologically or cytologically confirmed resectable mucosal melanoma. Only cases where a complete surgical resection with tumour-free margins can safely be achieved, as assessed by the surgeon, are defined as resectable.

  4. Newly diagnosed melanoma without any previous anti-cancer treatment 5. Patients must be able to provide a biopsy at baseline 6. Able to swallow and retain oral medication 7. Be medically fit enough to undergo surgery as determined by the treating medical and surgical oncology team 8. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days of treatment initiation.

  9. Demonstrate adequate organ function as defined in Table 1. All screening labs should be performed within 1 week prior to treatment initiation.

  10. 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 before treatment initiation.

  11. Males and female subjects of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study medication.

  12. (Female subject of childbearing potential) Have a negative urine or serum pregnancy test within 1 week prior to receiving the first dose of study medication. If the urine test is positive or borderline a serum pregnancy test will be required.

Exclusion Criteria:

• 1. Has a known additional malignancy that is progressing or requires active treatment, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.

  2. Has known central nervous system (CNS) metastases and/or carcinomatous meningitis.

  3. Has received any prior systemic anti-cancer treatment for melanoma 4. Has received prior lenvatinib 5. Has received prior therapy with an anti-PD-1 or anti-PD-L1 agent 6. Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 4 weeks of the first dose of treatment in this current trial.

Note: subject should be excluded if he/she received an investigational agent with anti-cancer or anti-proliferative intent within the last 12 months.

7. Has received a live vaccine within 30 days of the first dose of study treatment.

Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., FluMist ®) are live attenuated vaccines, and are not allowed.

8. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.

9. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 1 week prior to the first dose of trial treatment.

10. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

11. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

12. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis 13. Has an active infection requiring systemic therapy. 14. Has presence of gastrointestinal condition including malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib.

15. Has had a major surgery within 4 weeks prior to initiation of treatment. Adequate wound healing after major surgery must be assessed clinically and have resolved completely.

16. Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.

17. Has radiographic evidence of major blood vessel invasion/infiltration. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.

18. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug.

19. Has clinically significant cardiovascular disease within 12 months of the first dose of study intervention including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.

Note: Medically controlled arrhythmia would be permitted. 20. Has urine protein ≥1 g/24-hour. Note: Participants with >1+ proteinuria on urine dipstick will undergo 24-hour urine collection for quantitative assessment of proteinuria.

21. Has prolongation of QTc interval (calculated using Fridericia's formula) to >480 msec.

22. Has left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multi-gated acquisition scan (MUGA) or echocardiogram.

23. Has a history or current evidence of any condition, therapy, lab abnormality or other circumstance that might expose the subject to risk by participating in the trial, confound the results of the trial, or interfere with the subject's participation for the full duration of the trial.

24. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

25. Is pregnant or breastfeeding or expecting to conceive children within the projected duration of the trial, starting with the screening visit through 6 months after the last dose of study medication.

26. Has a known hypersensitivity to the components of the study therapy or its analogs.

27. Has a known history of active TB (Bacillus Tuberculosis) Female participants who are breastfeeding are not eligible for enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Lenvatinib and Pembrolizumab in Resectable mucosal Melanoma.

Drug: Lenvatinib, Pembrolizumab; After enrollment, patients receive pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for 6 weeks; Lenvatinib 20mg orally once daily for 6 weeks. Patients conduct surgery within 1-4 weeks after the last dose of Pembrolizumab and Lenvatinib. After complete surgery, Pembrolizumab will be as adjuvant treatment for up to 15 cycles, 200mg IV on day 1 of every 21 day-cycles.; Other Names: Biological: Pembrolizumab IV infusion Other Names: MK-3475; KEYTRUDA®; Drug: Lenvatinib Oral capsule Other Names: MK-7902; E7080; LENVIMA®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response (pCR) rate: defined as the percentage of subjects without alive tumor cells in the resected specimen post operation.	To evaluate pathological complete response (pCR) rate of Pembrolizumab combined with Lenvatinib as neoadjuvant therapy for resectable mucosal melanoma.	Approximately 10 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of AEs/SAEs	Adverse events (AEs) ; serious adverse events (SAEs); abnormal value of Lab test according to NCI-CTCAE V5.0	Approximately 2 years
1 year RFS (recurrence-free survival) rate per RECIST1.1 as Assessed by investigator	To evaluate1-year RFS rate of Pembrolizumab combined with Lenvatinib as neoadjuvant therapy for resectable mucosal melanoma.	Approximately 1 year
Overall survival	OS is defined as the time from date of randomization to date of death from any cause. OS will be presented.	Approximately 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The time from surgery completion to wound healing	To evaluate pembrolizumab with Lenvatinib as neoadjuvant treatment impact on surgery outcome	Approximately 12 weeks

Collaborators and Investigators

• Sponsor: Peking University Cancer Hospital & Institute

Study record dates

Study Major Dates

• Study Start (Anticipated): December 30, 2020
• Primary Completion (Anticipated): December 30, 2021
• Study Completion (Anticipated): December 30, 2023

Study Registration Dates

• First Submitted: October 28, 2020
• First Submitted That Met QC Criteria: November 9, 2020
• First Posted (Actual): November 10, 2020

Study Record Updates

• Last Update Posted (Actual): November 13, 2020
• Last Update Submitted That Met QC Criteria: November 10, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Lenvatinib; pembrolizumab
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Pembrolizumab; Lenvatinib
• Other Study ID Numbers: MK59132

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes