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Carcinoma, Merkel Cell

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Merkel Cell Carcinoma

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All Drugs and Chemicals

Avelumab

Antineoplastic Agents, Immunological

Participants with metastatic Merkel cell carcinoma (MCC) after failing first-line chemotherapy received Avelumab at a dose of 10 milligram per kilogram (mg/kg) as 1-hour intravenous infusion once every 2 weeks until therapeutic failure, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product occurs.

Participants received Avelumab as first-line treatment for metastatic or distally recurrent MCC at a dose of 10 mg/kg as 1-hour intravenous infusion once every 2 weeks until therapeutic failure, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product occurs.

Avelumab was administered at a dose of 10 milligram per kilogram (mg/kg) as 1-hour intravenous infusion once every 2 weeks until therapeutic failure, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product occurs.

Medical Responsible

This is a multicenter, international, single-arm, open-label, Phase 2 trial to evaluate the efficacy and safety of avelumab in participants with metastatic Merkel cell carcinoma (MCC).

Avelumab in Participants With Merkel Cell Carcinoma (JAVELIN Merkel 200)

A Phase II, Open-Label, Multicenter Trial to Investigate the Clinical Activity and Safety of Avelumab (MSB0010718C) in Subjects With Merkel Cell Carcinoma

Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, EMD Serono will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.emdgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html

Confirmed BOR was determined according to RECIST 1.1and as adjudicated by an Independent Endpoint Review Committee(IERC) and defined as best response of any of complete response (CR), partial response(PR), stable disease(SD) and progressive disease(PD) recorded from date of randomization until disease progression/recurrence(taking smallest measurement recorded since start of treatment as reference). CR:Disappearance of all evidence of target/non-target lesions. PR:At least 30%reduction from baseline in sum of longest diameter(SLD) of all lesions. SD:Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD:at least a20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1or more new lesions and unequivocal progression of non-target lesions. CR or PR must be confirmed by a subsequent tumor assessment preferably at next scheduled 6-weekly assessment, but no sooner than 5 weeks after initial documentation of CR or PR.

Durable response is defined as an objective response (confirmed complete response \[CR\] or confirmed Partial response \[PR\]) according to Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1, determined by the Independent Endpoint Review Committee (IERC), with a duration of at least 6 months. The DRR was determined as the percentage of participants with an objective response in terms of CR or PR according to RECIST 1.1, as determined by the IERC, with a duration of at least 6 months. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions.

The duration of response as determined from IERC tumor assessment was calculated for each participant with a confirmed response (CR or PR) as the time from first observation of response until first observation of documented disease progression or death when death occurs within 12 weeks of the last tumor assessment, whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Results were calculated based on Kaplan-Meier estimates.

The PFS time (based on IERC tumor assessments), according to the RECIST 1.1, was defined as the time from first administration of study treatment until first observation of PD or death when death occurred within 12 weeks of the last tumor assessment or first administration of study treatment (whichever was later). PFS time (in months) was defined as: (date of PD or death - date of the first dose of study treatment + 1)/30.4375 (months). PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions and unequivocal progression of non-target lesions.

Related Adverse events (AE) were defined according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE) as adverse events with relationship to study treatment reported by the investigator. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state up to 30 days after last administration. TEAEs included both Serious TEAEs and non-serious TEAEs. Related TEAEs are defined as events with a relationship of missing, unknown, or yes.

The laboratory measurements included hematology, liver function and blood chemistry. Number of participants with clinically significant abnormalities with Grade greater than or equals to (\>=) 3 in laboratory values reported as TEAEs were reported. Clinically Significance was decided by investigator.

Vital signs including body temperature, body weight, respiratory rate, heart rate (after 5-minute rest), and arterial blood pressure (after 5-minute rest) were evaluated. Number of participants with clinically significant abnormalities in Vital Signs reported as TEAEs. Clinically Significance was decided by investigator.

A 12-lead ECG was recorded after the participant has been in a supine position breathing quietly for 5 minutes. The ECG results was used to evaluate the heart rate, atrial ventricular conduction, PR interval, QRS, QTcF and QTcB. Number of participants with clinical significant abnormalities in ECG parameter reported here. Clinically Significance was decided by investigator.

The OS time was defined as the time from first administration of trial treatment until death. The OS time was analyzed using the Kaplan-Meier method.

The response status at 6 and 12 months after start of trial treatment according to RECIST 1.1 (as determined by the IERC) was determined. A participant was considered to be in response at the given timepoint (6 or 12 months after the start of the participant's treatment) if the participant had a documented response (PR or CR) prior to that timepoint, and neither died nor experienced disease progression according to the RECIST 1.1 nor was lost to follow-up up to the given timepoint. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Percentage of participants in response and not in response according to RECIST1.1 at 6 and 12 months were reported.

Serum samples were analyzed by a validated electrochemiluminesce immunoassay to detect the presence of anti-avelumab antibodies. Samples that screened positive were subsequently tested in a confirmatory assay. Those confirmed positive were titered for a quasi-quantitative result. Number of participants with positive treatment emergent anti-Avelumab antibodies were reported. Participants not positive prior to treatment with avelumab and with at least one positive result in the human-Antihuman Antibodies assay were characterized as treatment-emergent.

Serum concentration at end of infusion (CEOI) of Avelumab is reported.

Minimum serum post-dose (Ctrough) concentration of avelumab was reported.

The OS time was defined as the time from first administration of study treatment until the date of death. OS was calculated using following formula = (date of death - date of the first dose of study treatment + 1)/30.4375 (months).

The duration of response as determined from IERC tumor assessment was calculated for each participant with a confirmed response (CR or PR) as the time from first observation of response until first observation of documented disease progression or death when death occurs within 12 weeks of the last tumor assessment, whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions.

Serum samples were analyzed by a validated electrochemiluminescence immunoassay to detect the presence of antidrug antibodies (ADA). Samples that screened positive were subsequently tested in a confirmatory assay. Those that confirmed positive were titered for a quasi-quantitative result. Number of participants with positive treatment emergent anti-Avelumab antibodies were reported. Participants not positive prior to treatment with avelumab and with at least one positive result in the human-Antihuman Antibodies assay were characterized as treatment-emergent.

EMD Serono Research & Development Institute, Inc.

Adverse events were reported as per MedDRA v21.1 for Part A arm and MedDRA v22.0 for Part B.

Part A: Avelumab

Part B: Avelumab

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Communication Center

Complete Response

Partial Response

Stable Disease

Non-complete Response/ Non-progressive Disease

Progressive Disease

Not evaluable

Intent-to-Treat analysis set included all participants who received at least 1 dose of study treatment.

Part A: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1

Full analysis set (FAS) included all participants who received at least 1 dose of study treatment.

Part B: Durable Response Rate (DRR)

Intent-to-Treat analysis set included all participants who received at least 1 dose of study treatment. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Part A: Duration of Response According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1

Part A: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1

Participants with TR-TEAEs

Participants with TR-Serious-TEAEs

Participants with TR-TEAEs leading to Death

Safety analysis set included all participants who received at least 1 dose of study treatment.

Part A: Number of Participants With Treatment-Related (TR) Treatment-Emergent Adverse Events (TEAEs), Treatment-Related Serious TEAEs and Treatment-Related TEAEs Leading to Death

Anemia

Lymphocyte count decreased

Neutrophil count decreased

Platelet count decreased

White blood cell count decreased

Hypoalbuminemia

Alkaline phosphatase increased

Alanine aminotransferase increased

Serum amylase increased

Aspartate aminotransferase increased

Blood bilirubin increased

Cholesterol high

Creatine phosphokinase increased

Creatinine increased

Chronic kidney disease

Gamma-glutamyltransferase increased

Hyperglycemia

Hypoglycemia

Hyperkalemia

Hypokalemia

Lipase increased

Hypermagnesemia

Hypophosphatemia

Hyponatremia

Hypertriglyceridemia

Part A: Number of Participants With Clinically Significant Abnormalities in Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)

Body temperature Increased

Weight Increased

Weight Decreased

Increased Heart Rate

Decreased Heart Rate

Increased Systolic Blood Pressure

Decreased Systolic Blood Pressure

Increased Diastolic Blood Pressure

Decreased Diastolic Blood Pressure

Increased Respiratory Rate

Decreased Respiratory Rate

Part A: Number of Participants With Clinically Significant Abnormalities in Vital Signs Reported as Treatment Emergent Adverse Events (TEAEs)

PR interval >= 220 ms

QRS >= 120 ms

QTcF > 30 ms and <= 60 ms

QTcF > 60 ms

QTcB > 30 ms and <= 60 ms

QTcB > 60 ms

Heart rate <= 50 bpm

Heart rate >= 120 bpm

Safety analysis set included all participants who received at least 1 dose of study treatment. Here "Number of participants analyzed" signifies those who were evaluable for this outcome measure.

Part A: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG)

Part A: Interim Analysis: Overall Survival (OS) Time

Part A: Final Analysis: Overall Survival (OS) Time

In-response at Month 6

In-response at Month 12

Not in-response at Month 6

Not In-response at Month 12

Part A: Participant's Response Status According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 at 6 and 12 Months

Part A: Number of Participants With Positive Treatment Emergent Anti-Avelumab Antibodies

Day 1

Day 43

Day 85

Day 169

Day 253

Day 337

Day 421

Pharmacokinetic analysis set consists of all participants who received at least 1 dose of avelumab, and provide at least 1 measurable post-dose concentration. Here "Number analyzed" signifies those participants who were evaluable at specified timepoints

Part A: Serum Concentration at End of Infusion (CEOI) of Avelumab

Day 15

Day 29

Day 57

Day 71

Day 99

Day 211

Part A: Minimum Serum Post-dose (Ctrough) Concentration of Aveluamb

Full Analysis Set included all participants who received at least 1 dose of study treatment.

Part B: Interim Analysis: Overall Survival (OS) Time

Part B: Final Analysis: Overall Survival (OS) Time

Part B: Number of Participants With Confirmed Best Overall Response (BOR) as Per Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1

Full Analysis Set included all participants who received at least 1 dose of study treatment. Here "Number of participants analyzed" signifies those participants who were evaluable for this outcome measure.

Part B: Duration of Response According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1

Part B: Progression-Free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1

Part B: Number of Participants With Treatment-Related (TR) Treatment-Emergent Adverse Events (TEAEs), Treatment-Related Serious TEAEs and Treatment-Related TEAEs Leading to Death

Not in-response at Month 12

Part B: Participant's Response Status According to RECIST 1.1 at 6 and 12 Months

Full Analysis Set included all participants who received at least 1 dose of study treatment. Here "Number of Participants analyzed" signifies those participants who were evaluable for this outcome measure.

Part B: Number of Participants With Positive Treatment Emergent Anti-Avelumab Antibodies

PK Analysis Set included all participants who received at least 1 dose of avelumab, and provided at least 1 measurable post-dose concentration. Here "Number analyzed" signifies those participants who were evaluable at specified time-point for this outcome measure.

Part B: Serum Concentration at End of Infusion (CEOI) of Avelumab

Day 127

Day 505

Day 589

Day 673

Part B: Minimum Serum Post-dose (Ctrough) Concentration of Aveluamb

Overall Study

Somatostatin

Lanreotide

BEYLOT-BARY Marie

DUTRIAUX Carole

DALAC Sophie

DUPUY Alain

LEBBE Céleste

AVRIL Marie-Françoise

DALLE Stéphane

GUILLOT Bernard

VERNEUIL Laurence

DRENO Brigitte

HAINAUT-Wierzbicka Ewa

GROB Jean-Jacques

DEQUATREBARBES Julie

ZEHOU Ouidad

The purpose of this trial is to evaluate the efficacy of lanreotide on locally evolving and/or metastatic MCC in a national prospective multicentre phase II study (centres belonging to the skin cancer task force of the French Society of Dermatology namely "Groupe de Cancérologie Cutanée de la Société Française de Dermatologie"). This one-arm study, for which the primary endpoint is overall response to lanreotide, will follow an A'Hern plan in one step (A'Hern RP. Sample size tables for exact single-stage phase II designs. Stat Med 2001, 20:859-66) with main evaluation at 12 weeks on a population of 35 patients. The investigators make assumption that a 40% success rate at 3 months would be desirable, but if it was 20% or less the treatment would be unacceptable. It gives a trial size of 35 patients with a cut-off of 12 patients. Over 12 patients lanreotide will be considered as effective.

The lanreotide treatment (Somatuline LP 120 mg injected subcutaneously every 28 days) will be provided by IPSEN Pharma laboratory. An ancillary immunohistochemistry study on somatostatine receptors 2,3,5, dopamine receptors 1,2 and polyomavirus MCPyV will bring new data on this neuroendocrine tumour and potentially provide new therapeutic perspectives.

The results of this study may :

* determine whether somatostatin analogues may help to treat locally advanced and/or metastatic MCC;
* address whether there is a correlation between positive SPECT-CT (octreoscan) assessment and therapeutic response to lanreotide;
* evaluate the place of TEP-CT and SPECT-CT for MCC evaluation/staging;
* evaluate in future studies, with the ancillary data, other analogues or hybrid molecules;
* consider, if positive results are obtained from this study, somatostatin analogues as adjuvant treatment after surgery of primary MCC.

The efficacy will be considered as success if patient have a positive response to lanreotide.

Primary criterion Positive response at 3 months will be defined according to the RECIST 1.1 criteria (clinical and TDM evaluation will be done at 3 months): complete response (CR) or partial response (PR) or stable disease (SD) at 3 months.

Secondary Objectives:

* Assessment of the primary criterion at M6, M9, M12, M18 and M24
* Description of the overall survival and time to progression
* Assessment of the efficacy of the following radiological exams for staging the disease: SPECT-CT and TEP-CT
* Description of the correlation of SPECT-CT results (positivity or negativity) and response to treatment, and the correlation of TEP-CT results and response to treatment
* Description of the safety and tolerability of lanreotide in this study

Population and Methods

Experimental plan French national prospective multicentre phase II one-arm study. This one-arm study, for which the primary endpoint is overall response to lanreotide, will follow an A'Hern plan in one step.

Population Inclusion criteria

* Histologically confirmed neuroendocrine carcinoma of the skin (Merkel cell carcinoma) with inoperable local-regional disease or distant metastatic disease (stages IIIB or IV AJCC 2010), cerebral nervous system metastases will be allowed.
* First line of treatment or more
* Measurable disease: at least 20 mm by conventional techniques or 10 mm by spiral CT scan
* Age 18 years or older;
* WHO performance status ECOG 0-3
* premenopausal patients must use effective contraception
* No other prior malignancy within 5 years except adequately treated basal cell or squamous cell carcinoma or in situ cancer of the cervix
* No other concurrent chemotherapy, immunotherapy or hormone therapy.
* At least 4 weeks since adjuvant chemotherapy, 14 days since radiotherapy and 2 weeks since surgery
* Biological functions: absolute neutrophil count at least 1000/mm3, platelet count at least 100000/mm3, haemoglobin at least 9g/dl (transfusion allowed), bilirubin no greater than 3 times upper limit of normal (ULN), SGOT and SGPT no greater than 2.5 times ULN, no untreated chronic liver disease, creatinine no greater than 1.5 times ULN, no untreated chronic renal disease, no untreated diabetes or infection
* Written informed consent

Exclusion criteria

* previous hypersensibility to lanreotide treatment
* complicated and untreated cholelithiasis
* pregnancy or breast-feeding
* patient treated with cyclosporine

Studied treatment Lanreotide 120 mg sub-cutaneously every 28 days during 12 weeks, followed by injections every 28 days if response is positive until progression. The expected rate of positive response is 50% of patients at 3 months and 25% of patients at 1 year.

Evaluation Criteria and follow-up of the study The inclusions will be done during 2 years and the follow-up of patients is planned to be 2 years, to have an optimal assessment of progression free survival in case of response to treatment, with a total study duration of 4 years.

Data collection

* at inclusion : patient's demography and medical history; clinical and anatomopathological data on primary MCC; blood count, platelets, electrolytes, glucose, creatinine, transaminases, bilirubin, ECG, pregnancy test for women of childbearing age;
* Clinical examination and measure of possible target lesions (tumor and cutaneous metastasis) using RECIST 1.1 criteria at inclusion and at M1, M2 and M3 and every 3 months during the first year (M6, M9 and M12) and every 6 months during the second year of follow-up (M18 and M24);
* Cerebral and thoraco-abdominal CTscan with results of imaging (RECIST 1.1 criteria: http://www.recist.com/recist-in-practice/01.html) at inclusion, at 3 months and, every 3 months during the first year, every 6 months during 2nd year;
* Octreoscan (SPECT-CT) at inclusion
* PET-CT at inclusion

Treatment of Unresecable and/or Metastatic Merkel Cell Carcinoma by Somatostatine Analogues

Traitement Des Carcinomes à Cellules de Merkel inopérables et/ou métastatiques Par Analogue de la Somatostatine - Etude Nationale Multicentrique Mono-bras de Phase II.

Positive response will be defined according to the RECIST 1.1 criteria

Positive response will be defined according to the RECIST 1.1

Description of the safety and tolerability of lanreotide in this study

University Hospital, Grenoble

Skin and Connective Tissue Diseases

Skin Diseases

Subjects with a skin disease or at risk of developing a skin disease/ Family member of persons with a skin disease

Monica Taylor, R.N.

For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Avelumab in Participants With Merkel Cell Carcinoma (JAVELIN Merkel 200)	NCT02155647	Carcinoma, Merk...	Avelumab	18 Years -	EMD Serono
Treatment of Unresecable and/or Metastatic Merkel Cell Carcinoma by Somatostatine Analogues	NCT02351128	Carcinoma, Merk...	Lanreotide	18 Years -	University Hospital, Grenoble
Studies of Dermatologic Diseases Biospecimen Acquisition Protocol	NCT02471352	Dermatologic Co... Healthy Volunte... Normal Voluntee... Carcinoma, Merk...		1 Day - 100 Years	National Institutes of Health Clinical Center (CC)
Treatment of Unresecable and/or Metastatic Merkel Cell Carcinoma by Somatostatine Analogues	NCT02351128	Carcinoma, Merk...	Lanreotide	18 Years -	University Hospital, Grenoble

Spots Global Cancer Trial Database for carcinoma, merkel cell