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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT04207086




Registration number
NCT04207086
Ethics application status
Date submitted
17/12/2019
Date registered
20/12/2019
Date last updated
21/05/2020

Titles & IDs
Public title
A Phase II Study of Neoadjuvant Pembrolizumab & Lenvatinib for Resectable Stage III Melanoma
Scientific title
A Phase II, Open Label, Single Arm Study of Neoadjuvant Pembrolizumab and Lenvatinib for Patients With Resectable Stage III Melanoma
Secondary ID [1] 0 0
OTSP 57111
Secondary ID [2] 0 0
MIA/CT2019/281
Universal Trial Number (UTN)
Trial acronym
Neo PeLe
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Melanoma Stage III 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Pembrolizumab
Treatment: Drugs - Lenvatinib

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.


Treatment: Drugs: 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.

Treatment: Drugs: 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 (PDGFRa), stem cell factor receptor (KIT), and rearranged during transfection (RET).

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Pathological response rate - Proportion of patients with complete absence of residual melanoma cells in the the planned resected tumour site(s) at week 6 surgery.
Timepoint [1] 0 0
From baseline to 6 weeks planned resected tumour site(s) at week 6 surgery
Primary outcome [2] 0 0
The anti-tumoural immune response - 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.
Timepoint [2] 0 0
Baseline, week 1 week 6
Secondary outcome [1] 0 0
Objective clinical (RECIST) response rate - Proportion of patients with complete and partial responses at 6 weeks compared to baseline per RECIST guidelines for each treatment arm.
Timepoint [1] 0 0
From baseline to 6 weeks
Secondary outcome [2] 0 0
Metabolic response rate - Proportion of patients with complete and partial metabolic responses assessed by PET scan at 6 weeks compared to baseline for each treatment arm.
Timepoint [2] 0 0
From baseline to 6 weeks
Secondary outcome [3] 0 0
Relapse free survival - The amount of time that patients are disease free from the time of surgery at 6 weeks from study entry.
Timepoint [3] 0 0
5 years
Secondary outcome [4] 0 0
Treatment free survival - 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.
Timepoint [4] 0 0
1, 2, 3, 4 and 5 years from the end of adjuvant treatment
Secondary outcome [5] 0 0
Overall survival - The proportion of patients who are alive from the time of study entry
Timepoint [5] 0 0
5 years
Secondary outcome [6] 0 0
Incidence of post operative infection - 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.
Timepoint [6] 0 0
6 weeks
Secondary outcome [7] 0 0
Incidence of post operative seroma formation - 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.
Timepoint [7] 0 0
6 weeks
Secondary outcome [8] 0 0
Duration of post operative wound drainage time - The number of days that a wound drain remains in situ from the time of surgery.
Timepoint [8] 0 0
6 weeks
Secondary outcome [9] 0 0
Incidence of post operative bleeding requiring return to theatre or transfusion - 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.
Timepoint [9] 0 0
6 weeks
Secondary outcome [10] 0 0
Comparison of surgeon's opinion of operability evaluated at baseline to time of surgery - The change, if any, in the surgeon's assessment of 'operability' from baseline opinion (based on clinical and imaging examination) to time of operation.
Timepoint [10] 0 0
6 weeks
Secondary outcome [11] 0 0
Incidence of any treatment-emergent adverse events - 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.
Timepoint [11] 0 0
52 weeks
Secondary outcome [12] 0 0
Description of the morphological assessment of melanoma tissue - The effects of study treatment on the degree of necrosis and genetic markers in tumour tissue prior to surgery.
Timepoint [12] 0 0
Baseline, week 1, week 6
Secondary outcome [13] 0 0
Description of the RNA expression profile of melanoma tumour - The effects of study treatment on the baseline function of RNA expression in tumour tissue prior to surgery.
Timepoint [13] 0 0
Baseline, week 1, week 6
Secondary outcome [14] 0 0
Measurement of leucocyte subpopulations in peripheral blood - The effects of study treatment on the number and type of white cells in the blood.
Timepoint [14] 0 0
Baseline, week 1, week 6
Secondary outcome [15] 0 0
Measurement of circulating tumour DNA - The levels of melanoma DNA that is circulating in the blood stream and the changes during study treatment.
Timepoint [15] 0 0
Baseline, week 1, week 6
Secondary outcome [16] 0 0
Concordance of metabolic response measured by pathological response - 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.
Timepoint [16] 0 0
6 weeks
Secondary outcome [17] 0 0
Concordance of metabolic response measured by RECIST response - 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.
Timepoint [17] 0 0
52 weeks
Secondary outcome [18] 0 0
Concordance of pathological response measured by RECIST response - 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
Timepoint [18] 0 0
6 weeks
Secondary outcome [19] 0 0
Concordance of metabolic response with RECIST response at relapse - 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.
Timepoint [19] 0 0
52 weeks
Secondary outcome [20] 0 0
Quality of life scores - The individual, summary and composite scores obtained from the validated EUROQOL QLQ-C30, EQ-5D and FACT-M questionnaires
Timepoint [20] 0 0
At baseline, weeks 6, 15, 21, 27, 33, 39, 45, 51

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
115 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Melanoma Institute Australia - North Sydney
Recruitment postcode(s) [1] 0 0
2060 - North Sydney

Funding & Sponsors
Primary sponsor type
Other
Name
Melanoma Institute Australia
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Merck Sharp & Dohme Corp.
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT04207086
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Georgina V Long
Address 0 0
Melanoma Institute Australia
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Monica Osorio
Address 0 0
Country 0 0
Phone 0 0
+612 9911 7296
Fax 0 0
Email 0 0
Monica.Osorio@melanoma.org.au
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT04207086