- ICH GCP
- Registre américain des essais cliniques
- Essai clinique NCT03220009
Nivolumab or Expectant Observation Following Ipilimumab, Nivolumab, and Surgery in Treating Patients With High Risk Localized, Locoregionally Advanced, or Recurrent Mucosal Melanoma
A Randomized Phase II Trial of Adjuvant Nivolumab or Expectant Observation Following Neoadjuvant Ipilimumab Plus Nivolumab and Surgical Resection of High-Risk Localized, Locoregionally Advanced, or Recurrent Mucosal Melanoma
Aperçu de l'étude
Statut
Les conditions
- Carcinome du col de l'utérus
- Mélanome récurrent
- Carcinome vaginal
- Carcinome de l'œsophage
- Mélanome muqueux
- Mélanome muqueux de la tête et du cou
- Mélanome des muqueuses de la cavité buccale
- Cancer de la vulve de stade II AJCC v7
- Cancer de la vulve de stade III AJCC v7
- Cancer de la vulve de stade IIIA AJCC v7
- Cancer de la vulve de stade IIIB AJCC v7
- Cancer de la vulve de stade IIIC AJCC v7
- Stage IV Oral Cavity Cancer AJCC v6 and v7
- Stage IV Vulvar Cancer AJCC v7
- Cancer de la cavité buccale de stade IVA AJCC v6 et v7
- Cancer de la cavité buccale de stade IVB AJCC v6 et v7
- Stade IVC Cancer de la cavité buccale AJCC v6 et v7
Description détaillée
PRIMARY OBJECTIVES:
I. Recurrence free survival (RFS) in patients with mucosal melanoma (MM) treated with neoadjuvant ipilimumab plus nivolumab and surgery followed by adjuvant nivolumab and expectant observation.
SECONDARY OBJECTIVES:
I. Pathologic complete response with neoadjuvant ipilimumab plus nivolumab. II. Distant recurrence-free survival (DRFS) with adjuvant nivolumab and expectant observation.
III. Overall survival (OS) with adjuvant nivolumab and expectant observation. IV. Safety/toxicity as measured by maximum grade adverse event in (a) the neoadjuvant setting, (b) the adjuvant nivolumab cohort after randomization, and (c) the observation cohort after randomization.
V. Rate of delayed primary surgery.
TERTIARY OBJECTIVES:
I. Demonstrate that baseline tumors harboring a higher neoepitope burden have superior median RFS than those who have a lower neoepitope burden in the arm receiving adjuvant nivolumab.
II. Demonstrate that tumors with higher CD8+ infiltration at the tumor invasive margin at surgical resection have superior median RFS than those with lower CD8+ infiltration.
III. Demonstrate that tumors harboring a "T cell inflamed" ribonucleic acid (RNA) expression signature at surgical resection following neoadjuvant nivolumab plus ipilimumab have a superior distant RFS than those harboring a "non-T cell inflamed" signature, both in the overall group and within those who receive adjuvant nivolumab.
IV. Identify recurrent genetic alterations at baseline that are associated with higher CD8+/PD1+ infiltration at baseline and following 1 dose of neoadjuvant nivolumab plus ipilimumab.
V. Tumor response rate will be estimated based on patients whose imaging are captured and submitted during the neo-adjuvant portion of the study (imaging is not required).
OUTLINE:
PART I: Patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 30 minutes on day 1. Within 3-6 weeks after receiving nivolumab and ipilimumab, patients undergo surgery per standard of care. Within 84 days of last surgical resection, patients may also undergo adjuvant radiation therapy (RT), if clinically appropriate.
PART II: Within 84 days of last surgical resection, patients are randomized to 1 of 2 arms.
ARM I: Patients undergo active surveillance for 1 year.
ARM II: Patients receive nivolumab IV over 30 minutes once every 2 weeks for 4 doses. Patients then continue to receive nivolumab IV over 30 minutes once every 4 weeks for up to 11 doses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 90 days for 2 years, every 180 days for 3 years or until disease progression, whichever is first, and every 6 months thereafter until a maximum of 5 years following registration.
Type d'étude
Phase
- Phase 2
Contacts et emplacements
Lieux d'étude
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Massachusetts
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Boston, Massachusetts, États-Unis, 02115
- Alliance for Clinical Trials in Oncology
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-
Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
Accepte les volontaires sains
Sexes éligibles pour l'étude
La description
Inclusion Criteria:
- STEP 1 ELIGIBILITY CRITERIA
Documentation of disease:
- Histologic documentation: histologically proven mucosal melanoma by local pathology
- Tumor tissue: tumor tissue from the primary site of disease must be available for PD-L1 testing (stratification factor)
Disease status
- Tumors must have NOT been completely resected, or must be locoregionally recurrent if previously resected; tumor must be deemed potentially resectable by local surgeon
- MM arising from the head/neck, genitourinary, or gastrointestinal tract
Disease meets any 1 of 4 characteristics:
- Regional lymph node (LN) involvement; OR
- Multifocal/satellite primary disease; OR
Single localized, primary disease meeting one of the following site-specific requirements:
- Head/neck - any primary lesion if sinonasal; pT4a or above for nasal or oral cavity
- Anorectal - any primary lesion
- Conjunctiva - any primary lesion T2 or T3 stage by American Joint Committee on Cancer (AJCC)
- Vaginal/cervical - any primary
- Vulvar (hair bearing surface, labia majora) - AJCC cutaneous stage IIB or higher
- Esophageal - any primary
- Locoregionally recurrent following prior resection
- No evidence of metastatic disease at the time of registration
- No prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for MM, unless locoregionally recurrent; if recurrent, no prior medical or radiation therapy is allowed for the latest recurrence
No history of the following:
- Active known or suspected autoimmune disease
- Human immunodeficiency virus (HIV) with CD4+ count < 300 or detectable viral load; patients with HIV, undetectable viral load, and CD4+ count >= 300 are eligible
Known active hepatitis B or C
Hepatitis B can be defined as:
- Hepatitis B virus surface antigen (HBsAg) > 6 months
- Serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) 20,000 IU/ml (105 copies/ml), lower values 2,000-20,000 IU/ml (104-105 copies/ml) are often seen in hepatitis B virus e antigen (HBeAg)-negative chronic hepatitis B
- Persistent or intermittent elevation in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels
- Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation
Hepatitis C can be defined as:
- Hepatitis C antibody (AB) positive
- Presence of hepatitis C virus (HCV) RNA
- Known active pulmonary disease with hypoxia defined as oxygen saturation < 85% on room air
Not pregnant and not nursing
- For women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Absolute neutrophil count (ANC) >= 1,500/mm^3
- Platelet count >= 100,000/mm^3
- Creatinine clearance >= 30 mL/min by Modified Diet in Renal Disease (MDRD) equation or Cockcroft-Gault
Total bilirubin =< 1.5 x upper limit of normal (ULN)
- Except in case of Gilbert disease
- AST/ALT =< 2.5 x upper limit of normal (ULN)
Thyroid-stimulating hormone (TSH) within normal limits (WNL)
- Supplementation is acceptable to achieve a TSH WNL; in patients with abnormal TSH if free T4 is normal and patient is clinically euthyroid, patient is eligible
Concomitant medications
- No systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration (inhaled steroids for patients with underlying chronic pulmonary disease is acceptable as long as they meet other eligibility as listed above)
- No other planned concurrent investigational agents or other tumor directed therapy (chemotherapy, radiation) while on study
- STEP 2 ELIGIBILITY CRITERIA
Surgical resection of all gross disease
- This assessment will be made by the local investigator based on review of the operative report, pathology results, and/or radiology reports; microscopically positive margins (e.g. R1 resection) are permitted
Completion of PD-L1 testing
- Patients will be stratified as PD-L1 >= 5% versus (vs) < 5% OR inevaluable; baseline tumor will be utilized; if this returns inevaluable, efforts should be made to utilize the resected specimen
Randomization within 112 days of completion of surgical
- The primary region must be included on cross-sectional imaging (e.g. sinus/neck if arising from sinonasal primary; pelvis if genitourinary); radiographic changes considered nonspecific or possibly due to surgery or radiation are not considered evidence of disease
No significant immune-related adverse event due to the nivolumab plus ipilimumab dose received in the neoadjuvant setting, as follows:
- Any grade myocarditis, including an asymptomatic troponin elevation felt to be related to nivolumab plus ipilimumab
- Any grade neurologic complication (e.g. meningitis, encephalitis, neuropathy); study chair should be contacted if there is any question whether an adverse event (AE) was neurologic in nature
- Grade 2 or higher pneumonitis
- Grade 2 colitis
- Grade 2 or higher anemia (due to drug; unrelated anemia is not exclusionary)
- Thyroid/adrenal AEs regardless of grade that have stabilized or are clinically asymptomatic are eligible
- Fatigue, regardless of grade, is not a contraindication to randomization
- Grade 4 AST or ALT elevation
- Asymptomatic elevated amylase and lipase, regardless of grade, are not contraindications to randomization
Grade 4 rash; grade 3 rash is not a contraindication to randomization; any oropharyngeal lesions or bullous skin lesions that are suggestive of toxic epidermal necrolysis or Stevens-Johnson syndrome are contraindications to randomization regardless of the grade of rash
- If not specified above, other Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher AEs deemed possibly related to the nivolumab plus ipilimumab are exclusions to randomization; AEs that were attributable to surgery or adjuvant RT would not be contraindications to randomization
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: Randomisé
- Modèle interventionnel: Affectation parallèle
- Masquage: Aucun (étiquette ouverte)
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
---|---|
Comparateur actif: Arm I (nivolumab, ipilimumab, surgery, active surveillance)
PART I: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Within 3-6 weeks after receiving nivolumab and ipilimumab, patients undergo surgery per standard of care. Within 84 days of last surgical resection, patients may also undergo adjuvant RT, if clinically appropriate. PART II: Patients undergo active surveillance for 1 year. |
Études corrélatives
Étant donné IV
Autres noms:
Subir une RT
Autres noms:
Étant donné IV
Autres noms:
Subir une intervention chirurgicale
Faire l'objet d'une surveillance active
Autres noms:
|
Expérimental: Arm II (nivolumab, ipilimumab, surgery, nivolumab)
PART I: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Within 3-6 weeks after receiving nivolumab and ipilimumab, patients undergo surgery per standard of care. Within 84 days of last surgical resection, patients may also undergo adjuvant RT, if clinically appropriate. PART II: Patients receive nivolumab IV over 30 minutes once every 2 weeks for 4 doses. Patients then continue to receive nivolumab IV over 30 minutes once every 4 weeks for up to 11 doses in the absence of disease progression or unacceptable toxicity. |
Études corrélatives
Étant donné IV
Autres noms:
Subir une RT
Autres noms:
Étant donné IV
Autres noms:
Subir une intervention chirurgicale
|
Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
---|---|---|
Recurrence free survival (RFS)
Délai: From randomization to either adjuvant nivolumab or observation until evidence of disease recurrence, assessed up to 5 years
|
RFS of patients receiving adjuvant nivolumab will be compared to patients undergoing observation.
Kaplan- Meier curves will be constructed and median RFS times will be calculated for each arm.
|
From randomization to either adjuvant nivolumab or observation until evidence of disease recurrence, assessed up to 5 years
|
Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
---|---|---|
Distant recurrence-free survival (DRFS)
Délai: From randomization to either adjuvant nivolumab or observation until a distant recurrence is observed, assessed up to 5 years
|
Will be evaluated using the Kaplan- Meier method.
Median times to DRFS will be calculated for each arm and a cox proportional hazards model will be constructed to determine if there is a DRFS benefit for patients in the adjuvant Nivolumab arm (compared to observation).
|
From randomization to either adjuvant nivolumab or observation until a distant recurrence is observed, assessed up to 5 years
|
Incidence of adverse events evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Délai: Up to 5 years
|
Maximum grade adverse events will be summarized in each of the following settings: during the neo-adjuvant phase of the trial (i.e. from registration until a patient is randomized to adjuvant nivolumab or observation), the adjuvant nivolumab arm after randomization, he observation arm after randomization.
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Up to 5 years
|
Overall survival (OS)
Délai: From randomization to either adjuvant nivolumab or observation until death due to any cause; assessed up to 5 years
|
Will be evaluated using the Kaplan- Meier method.
Median OS times will be calculated for each arm and a cox proportional hazards model will be constructed to determine if there is a DRFS benefit for patients in the adjuvant Nivolumab arm (compared to observation).
|
From randomization to either adjuvant nivolumab or observation until death due to any cause; assessed up to 5 years
|
Rate of delayed surgery
Délai: Up to 6 weeks after registration
|
Reasons for delay will be summarized and the rate of delay will be calculated along with a 95% confidence interval using the properties of the binomial distribution.
|
Up to 6 weeks after registration
|
Autres mesures de résultats
Mesure des résultats |
Description de la mesure |
Délai |
---|---|---|
CD8+ infiltration
Délai: Up to 5 years
|
CD8+ infiltration levels will be compared to RFS times using a cox proportional hazards model.
|
Up to 5 years
|
Neoepitope burden
Délai: Up to 5 years
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Neoepitope burden will be compared to RFS using a cox proportional hazards model.
|
Up to 5 years
|
Pathologic complete response prior to surgery, for patients with imaging available
Délai: Up to time of surgery, assessed up to 5 years
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The rate of pathologic complete response will be estimated using and a 95% confidence interval will be calculated using properties of the binomial distribution.
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Up to time of surgery, assessed up to 5 years
|
Recurrent genetic alterations
Délai: Up to 5 years
|
Patients will be categorized by driver mutation, including BRAF, RAS family (NRAS/KRAS/HRAS), KIT, and/or NF1 alterations.
The degree of CD8+ and/or PD-L1 infiltration will be compared across various categories of driver mutation using descriptive statistics.
Pending further advances in genomic understanding of these tumors, alternate categories may be constructed.
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Up to 5 years
|
T cell inflammation
Délai: Up to 5 years
|
Patients will be categorized has having a "T dell inflamed" RNA expression signature versus a "non-T cell inflamed" signature.
These groups will be compared to each other in terms of RFS times using a cox proportional hazards model.
An additional model will be constructed with randomized arm included to determine if there is an interaction between signature and arm.
|
Up to 5 years
|
Collaborateurs et enquêteurs
Parrainer
Les enquêteurs
- Chercheur principal: Alexander Shoushtari, Alliance for Clinical Trials in Oncology
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude (Réel)
Achèvement primaire (Anticipé)
Achèvement de l'étude (Anticipé)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Réel)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Termes MeSH pertinents supplémentaires
- Maladies du système digestif
- Processus pathologiques
- Tumeurs par type histologique
- Tumeurs
- Tumeurs urogénitales
- Tumeurs par site
- Tumeurs, glandulaires et épithéliales
- Tumeurs génitales, femme
- Attributs de la maladie
- Tumeurs gastro-intestinales
- Tumeurs du système digestif
- Maladies gastro-intestinales
- Tumeurs de la tête et du cou
- Maladies stomatognathiques
- Maladies de la bouche
- Tumeurs neuroectodermiques
- Tumeurs, cellules germinales et embryonnaires
- Tumeurs, tissu nerveux
- Maladies de l'oesophage
- Tumeurs neuroendocrines
- Nevi et mélanomes
- Maladies vaginales
- Maladies vulvaires
- Carcinome
- Récurrence
- Mélanome
- Tumeurs vulvaires
- Tumeurs de l'oesophage
- Tumeurs de la bouche
- Tumeurs vaginales
- Mécanismes moléculaires de l'action pharmacologique
- Agents antinéoplasiques
- Agents antinéoplasiques immunologiques
- Inhibiteurs de point de contrôle immunitaire
- Nivolumab
- Ipilimumab
Autres numéros d'identification d'étude
- NCI-2017-01239 (Identificateur de registre: CTRP (Clinical Trial Reporting Program))
- U10CA180821 (Subvention/contrat des NIH des États-Unis)
- A091603 (Autre identifiant: CTEP)
Informations sur les médicaments et les dispositifs, documents d'étude
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