Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Pharmaceutical Solutions

All Drugs and Chemicals

Antineoplastic Agents

Nivolumab

Ipilimumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Nivolumab 3 mg/kg solution intravenously every 2 weeks up to 6 doses in Induction period and 3 mg/kg solution intravenously every 2 weeks until disease progression, unacceptable toxicity, or withdrawal of consent in Continuation period for a maximum of 2 years from 1st study treatment in Induction Period 1.

Ipilimumab 3 mg/kg solution intravenously every 3 weeks up to 4 doses in Induction period.

Ipilimumab 3 mg/kg solution intravenously every 3 weeks up to 4 doses in Induction period.

Nivolumab 3 mg/kg solution intravenously every 2 weeks up to 6 doses in Induction period and 3 mg/kg solution intravenously every 2 weeks until disease progression, unacceptable toxicity, or withdrawal of consent in Continuation period for a maximum of 2 years from 1st study treatment in Induction Period 1.

Bristol-Myers Squibb

The purpose of this study is to evaluate the safety and efficacy of a sequential combination therapy of Nivolumab and Ipilimumab

In order to evaluate the potential synergistic activity of nivolumab and ipilimumab and also because there may be differences in biology between tumors which are stable or responding to therapy and those that are clinically progressing, this study, CA209064, looked at two sequential combination regimens in which the second agent is administered immediately after a pre-specified duration of therapy with the first agent and not delayed until the time of progression after the first agent. This sequential study design looked at pharmacodynamic changes during treatment with one agent which may predict clinical activity to subsequent treatment with the alternate agent. This was done because it has not been scientifically proven whether or not the order in which nivolumab and ipilimumab are given is clinically important.

Study of Nivolumab Given Sequentially With Ipilimumab in Subjects With Advanced or Metastatic Melanoma (CheckMate 064)

An Open-Label, Randomized, Phase 2 Study of Nivolumab Given Sequentially With Ipilimumab in Subjects With Advanced or Metastatic Melanoma

The percentage of participants with treatment-related grade 3-5 adverse events (AEs) is defined as the number of participants who experienced at least 1 treatment related grade 3 - 5 adverse event (AE) per national cancer institute common terminology criteria for adverse events (NCI CTCAE v4.0, any preferred term) with an onset date after or on first day of Induction Period #1 and not later than discontinuation date from Induction Period #2, divided by the total number of treated participants.

Adverse Event (AE) = any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may or may not have a causal relationship with treatment.

Treatment-related = having certain, probable, possible, or missing relationship to study drug.

Grade (Gr) 3=Severe Gr 4=Potentially Life-threatening or disabling Gr 5=Death

Response rate is defined as the number of participants who have a complete response (CR) or partial response (PR) at Week 25 per modified RECIST 1.1 criteria, with confirmation on the scheduled scan at Week 33 (or any subsequent scan performed at least 4 weeks after the Week 25 scan), divided by the total number of treated participants. Results of the tumor assessment at Week 13 or any unscheduled tumor assessment obtained prior to Week 25, except for baseline/screening tumor assessment, were not considered in the assessment of response rate at Week 25.

Duration of response (DOR) is defined as the time between the Week 25 date of response and the date of objectively documented disease progression as defined by modified RECIST 1.1 criteria or death, whichever occurs first. Median computed using Kaplan-Meier method.

Progression rate at a specific timepoint is defined as the number of participants who have Progressive Disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at that specific timepoint divided by the total number of treated participants. As specified by modified RECIST 1.1, the evaluation of PD at Week 13 and Week 25 used the baseline tumor assessment as reference. A participant who died without a reported prior progression was considered to have progressed on the date of death. Deaths before or at Week 13 are counted as progression outcome. Confidence interval is based on the Clopper and Pearson method.

Nivolumab 3 mg/kg Q2W IV over 60 min for up to 6 doses during Weeks 1 to 13 in Induction Period 1 followed by Ipilimumab 3 mg/kg Q3W IV over 90 min for up to 4 doses during Weeks 13 to 25 in Induction Period 2.

Nivolumab Followed by Ipilimumab

Ipilimumab 3 mg/kg Q3W IV over 90 min for up to 4 doses during Weeks 1 to 13 in Induction Period 1 followed by Nivolumab 3 mg/kg Q2W IV over 60 min for up to 6 doses during Weeks 13 to 25 in Induction Period 2.

Ipilimumab Followed by Nivolumab

Total

Age, Continuous

Sex: Female, Male

White

Black or African American

Asian

American Indian or Alaska Native

Native Hawaiian or Other Pacific Islander

Other

Race/Ethnicity, Customized

Bristol-Myers Squibb Study Director

Percentage of Participants With Treatment-Related Grade 3-5 Adverse Events (AEs) During the Induction Period (Period 1 and 2)

Investigator-Assessed Response Rate at Week 25

All treated participants with confirmed response at week 25

Investigator-Assessed Duration of Response (DOR)

Week 13

Week 25

Investigator-Assessed Rate of Progression

Overall Study

Infections

Symptoms and General Pathology

Carcinoma

Carcinoma, Squamous Cell

Carcinoma, Merkel Cell

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms, Squamous Cell

Head and Neck Neoplasms

Communicable Diseases

Polyomavirus Infections

Virus Diseases

DNA Virus Infections

Tumor Virus Infections

Carcinoma, Neuroendocrine

Adenocarcinoma

Merkel Cell Carcinoma

Hematinics

Pembrolizumab

Cemiplimab

Liver Extracts

Determine the recommended Phase 2 dose of cavrotolimod in combination with pembrolizumab.

Determine the safety and preliminary efficacy of cavrotolimod and pembrolizumab in patients with advanced Merkel cell carcinoma that have progressed on an anti-PD-1 / anti-PD-L1 therapy.

Determine the safety and preliminary efficacy of cavrotolimod and cemiplimab in patients with advanced cutaneous squamous cell carcinoma that have progressed on an anti-PD-1.

Determine the safety and preliminary efficacy of cavrotolimod and pembrolizumab in patients with advanced Merkel cell carcinoma that have progressed on anti-PD-1 / anti-PD-L1 therapy.

Determine the safety and preliminary efficacy of cavrotolimod and pembrolizumab in patients with no cutaneous, subcutaneous, or accessible nodal tumor lesions amenable that have progressed on anti-PD-1 / anti-PD-L1 therapy.

Determine the safety and preliminary efficacy of cavrotolimod and pembrolizumab in patients with locally Advanced or Metastatic Melanoma that have progressed on anti-PD-1 / anti-PD-L1 therapy.

Determine the safety and preliminary efficacy of cavrotolimod and pembrolizumab in patients with metastatic solid tumors with liver metastases that have progressed on anti-PD-1 / anti-PD-L1 therapy.

Cavrotolimod

Pembrolizumab dosing as per the US prescribing information.

Cemiplimab dosing as per the US prescribing information.

Exicure Inc.

This is a phase 1b/2, open-label, two-part, multicenter trial designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of intratumoral cavrotolimod injections alone and in combination with intravenous pembrolizumab or cemiplimab in patients with Merkel Cell Carcinoma, cutaneous squamous cell carcinoma, and advanced solid tumors.

Phase 1b of this trial is a 3+3 dose escalation study evaluating escalating or intermediate dose levels of cavrotolimod given with a fixed dose of pembrolizumab.

The Phase 2 dose expansion part of the study will consist of two primary cohorts of patients: Merkel cell carcinoma and cutaneous squamous cell carcinoma. Patients in the Merkel Cell Carcinoma cohort will receive IT cavrotolimod combined with a fixed, standard dose of pembrolizumab while the Cutaneous Squamous Cell Carcinoma cohort will receive IT cavrotolimod combined with a fixed, standard dose of cemiplimab. The Phase 2 dose expansion is designed to provide a preliminary estimate of efficacy in patients that have progressed on an anti-PD-(L)1 CPI.

This study will be conducted in 2 phases. Phase 1 evaluates cavrotolimod given in combination with pembrolizumab in patients with advanced solid tumors in a classical 3+3 dose escalation design, with up to five ascending dose cohorts of cavrotolimod and enrollment of at least 3 patients per cohort to identify an RP2D. Patients will be dosed twice with cavrotolimod as a monotherapy before adding pembrolizumab, which will be added starting at the second cycle. Once the MTD or highest escalation cohort has been reached, or notable efficacy has been observed at a given dose level, and a decision as to a RP2D has been made, a two 2-stage expansion cohort design will be initiated.

Phase 2 will evaluate the RP2D of cavrotolimod given in combination with pembrolizumab or cemiplimab in two expansion cohorts following a modified Simon 2-stage optimal design comprised of patients with Merkel cell carcinoma or cutaneous squamous cell carcinoma. who previously received and have progressed on an anti-PD-(L)1 CPI. Patients in the Merkel Cell Carcinoma cohort will receive IT cavrotolimod combined with a fixed, standard dose of pembrolizumab while the Cutaneous Squamous Cell Carcinoma cohort will receive IT cavrotolimod combined with a fixed, standard dose of cemiplimab.

Phase 2 will include an exploratory expansion cohort to evaluate cavrotolimod in combination with pembrolizumab in patients with other advanced solid tumors, including melanoma, who have progressed on anti-PD-(L)1 therapy.

Exploratory expansion cohorts will evaluate patients with melanoma and additional patients with Merkel Cell Carcinoma who do not meet criteria for enrollment in the primary Merkel Cell Carcinoma cohort. In addition, two exploratory cohorts have been added to evaluate patients with advanced solid tumors and no superficial tumor accessible for IT injection using subcutaneously administered cavrotolimod or IT injection into liver metastases.

A cohort of up to 10 evaluable patients with locally advanced or metastatic solid tumors with no cutaneous, subcutaneous, or accessible nodal tumor lesions available for IT injection may be enrolled (inclusion criterion #4). The inclusion/exclusion criteria for this exploratory cohort will otherwise be the same as those used for the Phase 2 dose expansion cohorts except these patients will not be required to have a lesion accessible for biopsy (inclusion criterion #5). Patients will be dosed with cavrotolimod subcutaneously at a dose not to exceed the recommended Phase 2 dose, 32 mg, in combination with pembrolizumab.

Intratumoral Cavrotolimod Combined With Pembrolizumab or Cemiplimab in Patients With Merkel Cell Carcinoma, Cutaneous Squamous Cell Carcinoma, or Other Advanced Solid Tumors

Merkel Cell Carcinoma, Cutaneous Squamous Cell Carcinoma, or Other Advanced Solid Tumors: A Phase 1b/2 Study of Cavrotolimod Combined With Pembrolizumab or Cemiplimab

Individual participant data that underlie the results reported in the article, after de-identification (text, tables, figures, and appendices) will be shared to researchers who provide a methodologically sound proposal and sign a data access agreement.

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

To recommend a dose of cavrotolimod and combination regimen for further development

ORR to be calculated overall and by cohort/subgroup using RECIST v1.1. Subgroups will be defined for the efficacy analyses based on prior exposure and response to immune checkpoint inhibitors.

IHC on FFPE biopsies will be used to assess markers.

Selected gene-expression profiling on gene expression will be performed with nCounter (NanoString Technologies).

Exicure, Inc.

Behaviors and Mental Disorders

Quality of Life

Immunomodulating Agents

All patients included in this study will receive approved immune-checkpoint inhibitors therapies, such as CTLA-4, PD-1, and PD-L1 inhibitors.

immune-checkpoint inhibitors therapies

Dominique GENRE, MD

Margot BERLINE, MSc, MBA

Elodie Crétel

Renaud SABATIER, MD

Pierre SOUBEYRAN, Dr

Christelle LEVY, Dr

Christelle LEVY

Leila BENGRINE-LEFEVRE

Laurence CRISTOL, MD

Michaël BRINGUIER, Dr

Emmanuelle BOURBOULOUX, MD

Loïc MOUREY, Dr

Renaud Sabatier, MD

The co-primary objectives will be to assess the safety and quality of life under treatment.

The co-primary objectives will be to assess the safety and quality of life under treatment. Secondary objectives will be evaluations of geriatric data modifications under treatment, efficacy (progression-free survival and overall survival), correlation between toxicity and efficacy, and comparison of the safety profiles between various immunotherapy regimens.

Another secondary objective will be the comparison between patients and clinicians symptom reporting. The investigators will also perform a pharmacokinetics analysis on PD1-monoclonal antibodies to improve the understanding of PD-1 inhibitors pharmacokinetics for the elderly population.

Finally, toxicity and efficacy will be compared to immunological parameters such as the description of tumor infiltrating lymphocytes, markers of immunosenescence and inflammation.

This is a national prospective phase 4, multi-centre, single arm, open-label cohort study to evaluate the safety and efficacy of immune checkpoint inhibitors-based therapies in elderly patients with advanced or metastatic melanoma or NSCLC.

Elderly Cancer PatIents, Safety and qualiTy of Life Under immunOtheraPies

Elderly Cancer PatIents Treated for Advanced or Metastatic Melanoma or NSCLC, Safety and qualiTy of Life Under immunOtheraPies: a Phase IV Trial

Description of adverse events' type, incidence, severity (CTCAE v.5.0), timing, seriousness, and relatedness. This endpoint will be based on the rate of grade ≥ 3 adverse events 18 weeks after treatment initiation, defined as medical assessment of safety including adverse events' type, incidence, severity (graded by the CTCAE\] v. 5.0), timing, seriousness, and relatedness. This will include clinical as well as biological toxicities such as liver and endocrine dysfunctions. All high grade adverse events will be taken into account.

Quality of life will be evaluated using the EORTC QLQ-C30 and QLQ-ELD14 questionnaires collected at inclusion and at every treatment cycles during the first 6 weeks, then every 6 weeks until treatment discontinuation. The proportion of patients with a decrease superior or equal to 10% for their global score between baseline and at 24 weeks after treatment initiation will be estimated.

Geriatric data assessment will be done at inclusion and every 6 weeks until treatment discontinuation. Exhaustive data will be collected at inclusion. The investigators will also assess the G-CODE (Geriatric Core Dataset), a recently described minimum geriatric data set (see SOFOG guidelines). G-CODE assessment will be repeated every 6 weeks during treatment and at treatment discontinuation. These data will be collected either by the geriatrician or trained clinical research nurses during geriatric consultation as part of geriatric follow-up, an integral part of the patient management.

Reminder of CTCAE version 5.0 will be completed by clinicians before every treatment cycle. Patients will also complete a language adapted version of patient-reported outcome PRO-CTCAE questionnaire. For all symptoms, the investigators will measure the proportion of pairs for which clinicians and patients gave an identical grade. The investigators will also measure the proportion of pairs that will disagree for each symptom by one point (e.g., patient grade 2 and clinician grade 1), and the proportion that will disagree by two or more points (e.g., patient grade 2 and clinician grade 4). The investigators will also record the number of symptoms for which each pair agreed.

Evaluation of Progression-free Survival (PFS) will be defined as the time from treatment beginning to radiological (according to the RECIST 1.1 criteria) or clinical progression of the disease as declared by the investigators, or death of any cause. Radiological evaluations will be performed every 6 weeks.

Overall Survival (OS) will be defined as the time from treatment beginning to death of any cause.

Correlation between occurrence of auto-immune adverse events (with a landmark time at week 18) and efficacy (PFS).

Safety profiles comparison according to treatment regimen (PD1-inhibitor monotherapy vs PD1- inhibitor/CTLA4-inhibitor combination vs CTLA-inhibitor monotherapy vs PDL1-inhibitor if available at time of trial beginning) will be performed by looking at the rate of grade 3 to 5 adverse events 18 weeks after treatment initiation for each therapy.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of Nivolumab Given Sequentially With Ipilimumab in Subjects With Advanced or Metastatic Melanoma (CheckMate 064)	NCT01783938	Advanced or Met...	Nivolumab Ipilimumab	18 Years -	Bristol-Myers Squibb
Study of Nivolumab Given Sequentially With Ipilimumab in Subjects With Advanced or Metastatic Melanoma (CheckMate 064)	NCT01783938	Advanced or Met...	Nivolumab Ipilimumab	18 Years -	Bristol-Myers Squibb
Intratumoral Cavrotolimod Combined With Pembrolizumab or Cemiplimab in Patients With Merkel Cell Carcinoma, Cutaneous Squamous Cell Carcinoma, or Other Advanced Solid Tumors	NCT03684785	Advanced or Met... Advanced or Met... Advanced or Met... Advanced or Met... Advanced or Met...	Cavrotolimod Pembrolizumab Cemiplimab Cavrotolimod	18 Years -	Exicure, Inc.
Elderly Cancer PatIents, Safety and qualiTy of Life Under immunOtheraPies	NCT03673332	Advanced or Met... Advanced or Met...	immune-checkpoi...	70 Years -	Institut Paoli-Calmettes

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