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A Phase II Study of Neoadjuvant Pembrolizumab & Lenvatinib for Resectable Stage III Melanoma (Neo PeLe)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04207086
Recruitment Status : Not yet recruiting
First Posted : December 20, 2019
Last Update Posted : May 21, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Melanoma Institute Australia

Brief Summary:
In many cancers, early stage diagnosis and early treatment offers the best chance of a prolonged recurrence free- and overall survival. In stage III/IV resectable melanoma, an opportunity exists to improve outcomes with the addition of neoadjuvant and adjuvant systemic therapy as an adjunct to surgery. Neoadjuvant clinical trials for resectable but bulky stage III/IV melanoma allows for the efficient and rapid evaluation of drug activity in humans utilising multiple clinical endpoints of metabolic, radiological and pathological response; relapse-free survival; overall survival.

Condition or disease Intervention/treatment Phase
Melanoma Stage III Drug: Pembrolizumab Drug: Lenvatinib Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II, Open Label, Single Arm Study of Neoadjuvant Pembrolizumab and Lenvatinib for Patients With Resectable Stage III Melanoma
Estimated Study Start Date : August 1, 2020
Estimated Primary Completion Date : March 1, 2021
Estimated Study Completion Date : March 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: 6 wk pembrolizumab & lenvatinib, surgery, 46 wk pembrolizumab
Neoadjuvant pembrolizumab & lenvatinib for 6 weeks followed by definitive surgery then adjuvant pembrolizumab alone for 46 weeks.
Drug: Pembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
Other Name: Keytruda

Drug: Lenvatinib
Lenvatinib is an oral potent multiple RTK inhibitor that selectively inhibits VEGF receptors, VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), fibroblast growth factor receptor (FGFR1-4), platelet derived growth factor (PDGFRα), stem cell factor receptor (KIT), and rearranged during transfection (RET).
Other Name: Lenvima




Primary Outcome Measures :
  1. Pathological response rate [ Time Frame: From baseline to 6 weeks planned resected tumour site(s) at week 6 surgery ]
    Proportion of patients with complete absence of residual melanoma cells in the the planned resected tumour site(s) at week 6 surgery.

  2. The anti-tumoural immune response [ Time Frame: Baseline, week 1 week 6 ]
    Changes in T cell tumour infiltration, tumour PD-L1 expression, melanoma antigen expression, presence of regulatory T cells, immunosuppressive cytokines, VEGF signalling and modulation of the tumour vasculature.


Secondary Outcome Measures :
  1. Objective clinical (RECIST) response rate [ Time Frame: From baseline to 6 weeks ]
    Proportion of patients with complete and partial responses at 6 weeks compared to baseline per RECIST guidelines for each treatment arm.

  2. Metabolic response rate [ Time Frame: From baseline to 6 weeks ]
    Proportion of patients with complete and partial metabolic responses assessed by PET scan at 6 weeks compared to baseline for each treatment arm.

  3. Relapse free survival [ Time Frame: 5 years ]
    The amount of time that patients are disease free from the time of surgery at 6 weeks from study entry.

  4. Treatment free survival [ Time Frame: 1, 2, 3, 4 and 5 years from the end of adjuvant treatment ]
    The proportion of patients who have not had a relapse of disease during study treatment and who have no requirement for new melanoma treatment from the end of adjuvant treatment period.

  5. Overall survival [ Time Frame: 5 years ]
    The proportion of patients who are alive from the time of study entry

  6. Incidence of post operative infection [ Time Frame: 6 weeks ]
    The number of patients (and the number of episodes) who develop a post operative infection of the surgical wound requiring intravenous antibiotics and/or wound drainage.

  7. Incidence of post operative seroma formation [ Time Frame: 6 weeks ]
    The number of patients (and the number of episodes) who develop a seroma at the surgical site that requires any intervention and the volume of seroma drainage.

  8. Duration of post operative wound drainage time [ Time Frame: 6 weeks ]
    The number of days that a wound drain remains in situ from the time of surgery.

  9. Incidence of post operative bleeding requiring return to theatre or transfusion [ Time Frame: 6 weeks ]
    The number of patients (and the number of episodes) who have a bleed from the post operative surgical wound that requires a blood transfusion or return to theatre to stop the bleeding.

  10. Comparison of surgeon's opinion of operability evaluated at baseline to time of surgery [ Time Frame: 6 weeks ]
    The change, if any, in the surgeon's assessment of 'operability' from baseline opinion (based on clinical and imaging examination) to time of operation.

  11. Incidence of any treatment-emergent adverse events [ Time Frame: 52 weeks ]
    The number of study treatment related adverse events of all Common Terminology Criteria for Adverse Events (CTCAE) grades from the time of starting study treatment to the time of permanent discontinuation of study treatment.

  12. Description of the morphological assessment of melanoma tissue [ Time Frame: Baseline, week 1, week 6 ]
    The effects of study treatment on the degree of necrosis and genetic markers in tumour tissue prior to surgery.

  13. Description of the RNA expression profile of melanoma tumour [ Time Frame: Baseline, week 1, week 6 ]
    The effects of study treatment on the baseline function of RNA expression in tumour tissue prior to surgery.

  14. Measurement of leucocyte subpopulations in peripheral blood [ Time Frame: Baseline, week 1, week 6 ]
    The effects of study treatment on the number and type of white cells in the blood.

  15. Measurement of circulating tumour DNA [ Time Frame: Baseline, week 1, week 6 ]
    The levels of melanoma DNA that is circulating in the blood stream and the changes during study treatment.

  16. Concordance of metabolic response measured by pathological response [ Time Frame: 6 weeks ]
    The activity of melanoma tissue assessed by the uptake of fludeoxyglucose (18F) in tumour cells viewed using positron emission tomography (PET) and how well this corresponds to the findings from the pathological examination of completely excised tumour tissue.

  17. Concordance of metabolic response measured by RECIST response [ Time Frame: 52 weeks ]
    The activity of melanoma tissue assessed by the uptake of fludeoxyglucose (18F) in tumour cells viewed using positron emission tomography (PET) and how well this corresponds to the assessment of tumour size and extent using computed tomography and magnetic resonance imaging scans.

  18. Concordance of pathological response measured by RECIST response [ Time Frame: 6 weeks ]
    The findings from the pathological examination of completely excised tumour tissue and how well this corresponds to the assessment of tumour size and extent using computed tomography and magnetic resonance imaging scans

  19. Concordance of metabolic response with RECIST response at relapse [ Time Frame: 52 weeks ]
    The activity of recurrent melanoma tissue assessed by the uptake of fludeoxyglucose (18F) in tumour cells viewed using positron emission tomography (PET) and how well this corresponds to the assessment of tumour size and extent using computed tomography and magnetic resonance imaging scans.

  20. Quality of life scores [ Time Frame: At baseline, weeks 6, 15, 21, 27, 33, 39, 45, 51 ]
    The individual, summary and composite scores obtained from the validated EUROQOL QLQ-C30, EQ-5D and FACT-M questionnaires


Other Outcome Measures:
  1. Concordance of immune related response criteria (irRC) with RECIST response [ Time Frame: Weeks 6 and 52 ]
    The application of two different criterion to establish the tumour burden as assessed with computed tomography and magnetic resonance imaging.

  2. Correlation of the gut microbiome with RECIST response to immunotherapy [ Time Frame: Baseline, Week 6, week 24, at relapse if this occurs within 5 years from study entry ]
    Characterisation of the bacterial diversity and composition in stool samples at baseline, prior to surgery at week 6, week 24 and at relapse.

  3. Correlation of intestinal permeability with treatment response and toxicity [ Time Frame: Baseline and during 52 weeks of treatment ]
    Degree of intestinal mucosal integrity measured by the ability of two non-metabolized sugar molecules (lactulose and mannitol) recovered in a urine sample collected over 6 hours following ingestion.

  4. Characterisation of self-reported dietary habits (including use of oral probiotics) and correlation with the gut microbiome [ Time Frame: Baseline ]
    Diet plays a significant role in shaping the intestinal microbiome. Nutrition may influence the gut microbiome and response to immunotherapy.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 115 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 1. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
  • 2. Male/female participants who are at least 18 years of age on the day of signing informed consent.
  • 3. Histologically confirmed diagnosis of resectable AJCC (8th edition) Stage IIIB, IIIC or IIID cutaneous or unknown primary melanoma (except for any in-transit or satellite metastases) will be enrolled in this study. Note:

    • At baseline, patients may have a primary melanoma in addition to nodal disease.
    • At baseline, there must be sufficient nodal +/- primary disease which is amenable to multiple excision or core biopsies biopsies.
    • "Resectable" disease is defined as having no significant vascular, central nervous system or bony involvement. Only cases where a complete surgical resection leading to tumour free margins and which is safely achieved is considered "resectable".
  • 4. Have measurable disease based on RECIST version 1.1 criteria: ≥ 10mm in the longest diameter for primary (if applicable) lesions and ≥ 15mm in the shortest diameter for lymph nodes.
  • 5. Have provided a newly obtained core or excisional biopsy of an affected lymph node lesion which has been not previously irradiated. Archival tissue from the primary melanoma (if applicable) will also be collected, if available, but is not a requirement for study entry.
  • 6. Able to swallow and retain oral medication.
  • 7. A male participant must agree to use a contraception during the treatment period and for at least and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period and for at least 120 days after the last dose.
  • 8. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

    • Not a woman of childbearing potential (WOCBP), OR
    • A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least and for at least 120 days after the last dose of study treatment.
  • 9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of first dose of study treatment.
  • 10. Have adequate organ function as defined by routine laboratory testing.
  • 11. Adequately controlled blood pressure, with or without anti-hypertensive medications, defined as ≤ 150/90 mmHg at screening and no change in anti-hypertensive medications within one week of the first dose of study treatment. Note: Patients who are taking ≥ 3 anti-hypertensive medications at baseline will require approval from the Lead Investigator prior to enrolment.
  • 12. Anticipated life expectancy of > 12 months.

Exclusion Criteria:

  • 1. A woman of childbearing potential (WOCBP) who has a positive urine pregnancy test within 72 hours prior to the first dose of study treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  • 2. 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.
  • 3. Has received prior treatment for melanoma including investigational agents within 4 weeks prior to first dose of study treatment. The following are permitted:

    • Surgery for primary or past stage III melanoma.
    • Prior adjuvant interferon or ipilimumab for resected stage II/III melanoma and have recovered to ≤ Grade 1 or baseline from any treatment related adverse effects.
  • 4. Has had major surgery within 3 weeks prior to first dose of study treatments. Note: adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility.
  • 5. Participants who have not recovered adequately from any toxicity from other anti- cancer treatment regimens.
  • 6. Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. Prior radiotherapy to the presenting tumour is prohibited.
  • 7. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
  • 8. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
  • 9. Has a diagnosis of immunodeficiency and is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first dose of study drug. The following are permitted:

    • Vitiligo,
    • Type I diabetes mellitus,
    • Residual autoimmune hypothyroidism on stable hormone replacement,
    • Resolved childhood asthma or atopy,
    • Psoriasis not requiring systemic treatment,
    • Autoimmune conditions which are not expected to recur in the absence of an external trigger.
  • 10. Has active autoimmune disease that has required systemic treatment in the past 12 months (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). The following are permitted:

    • Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc, Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if patient on a stable dose,
    • Non-absorbed intra-articular steroid injections are permitted.
  • 11. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. The following malignancies, if undergone successful definitive resection or curative treatment, are permitted:

    • Basal cell carcinoma of the skin
    • Squamous cell carcinoma of the skin
    • Carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy)
    • Prostatic intraepithelial neoplasia
    • In situ melanoma
    • Atypical melanocytic hyperplasia
    • Multiple primary melanomas
    • Other malignancies for which the patient has been disease free for 1 year.
  • 12. Has known CNS metastases and/or carcinomatous meningitis.
  • 13. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.
  • 14. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis or current interstitial lung disease.
  • 15. Has an active infection requiring systemic therapy.
  • 16. Has a known history of Human Immunodeficiency Virus (HIV).
  • 17. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
  • 18. Has a known history of active TB (Bacillus Tuberculosis).
  • 19. Current diagnosis of any gastrointestinal condition that might affect the absorption of lenvatinib (e.g. malabsorption syndrome, gastrointestinal anastomosis, bariatric surgery).
  • 20. Has a pre-existing ≥ Grade 3 gastrointestinal or non-gastrointestinal fistula.
  • 21. History of, or current cardiovascular disease including: Uncontrolled arrhythmias associated with haemodynamic instability, Uncontrolled arrhythmias requiring medical treatment at screening, Unstable angina within 6 months of the first dose of study drug, myocardial infarction within 6 months of the first dose of study drug

    • >NYHA grade 2 congestive cardiac failure
    • Uncontrolled and treatment refractory hypertension systolic > 150 mmHg and/or diastolic > 90 mmHg in spite of an optimized regimen of antihypertensive medication(s).
    • Cerebrovascular accident within 6 months of the first dose of study drug
  • 22. Has a history of, or a current bleeding or thrombotic disorders or participants at risk for severe haemorrhage. The degree of tumour invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe haemorrhage associated with tumour shrinkage/necrosis following lenvatinib therapy.
  • 23. Participants with a >1+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is <1 g/24 hours.
  • 24. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
  • 25. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • 26. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04207086


Contacts
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Contact: Monica Osorio +612 9911 7296 Monica.Osorio@melanoma.org.au
Contact: Maria Gonzalez +612 9911 7200 maria.gonzalez@melamona.org.au

Locations
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Australia, New South Wales
Melanoma Institute Australia
North Sydney, New South Wales, Australia, 2060
Sponsors and Collaborators
Melanoma Institute Australia
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Georgina V Long Melanoma Institute Australia
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Responsible Party: Melanoma Institute Australia
ClinicalTrials.gov Identifier: NCT04207086    
Other Study ID Numbers: MIA/CT2019/281
OTSP 57111 ( Other Identifier: Merck Sharp & Dohme )
First Posted: December 20, 2019    Key Record Dates
Last Update Posted: May 21, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Melanoma Institute Australia:
Neoadjuvant therapy
Adjuvant therapy
Pembrolizumab
Lenvatinib
Pathological response
RECIST response
Metabolic response
Translational research
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Pembrolizumab
Lenvatinib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action