A study to evaluate Nivolumab and Ipilimumab for 2nd line therapy in elderly patients with advanced esophageal cancer

Phase 1

• Conditions: advanced esophageal squamous cell cancer; MedDRA version: 20.1Level: PTClassification code 10062878Term: Gastrooesophageal cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1Level: PTClassification code 10055102Term: Oesophageal cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: LLTClassification code 10015362Term: Esophageal cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: LLTClassification code 10030151Term: Oesophageal cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: LLTClassification code 10015363Term: Esophageal cancer NOSSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: LLTClassification code 10030152Term: Oesophageal cancer NOSSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: LLTClassification code 10056267Term: Gastroesophageal cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1Level: LLTClassification code 10062478Term: Esophageal cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2017-002056-86-DE
• Lead Sponsor: AIO-Studien-gGmbH

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2017-10-17
• Last Update Posted: 14 March 2022

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 75

Inclusion Criteria

1. Written informed consent including participation in translational research and any locally-required authorization (EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
2. Age = 65 years at time of study entry
3. Histologically confirmed advanced stage non-resectable esophageal squamous cell carcinoma beyond frontline therapy*:
• stage 4 OR
• stage 3 non-responder to radio-chemotherapy OR
• any relapse after chemo-radiation OR
• any relapse after surgery if patient is ineligible or intolerant to standard frontline therapies OR refuses other treatment
* Frontline therapy is defined as chemotherapy (+/-radiotherapy) (e.g. CROSS, FLOT or similar protocols) OR any palliative systemic chemotherapy
4. Geriatric status: SlowGo or GoGo according to G8 and DAFI assessment (G8 > 14 points or CGA/DAFI 0.2<0.35)
5. At least 1 measurable lesion according to RECIST 1.1
6. Karnofski performance status = 50
7. Sufficient cardiac functional reserve defined as ejection fraction = 50%
9. Adequate blood count, liver-enzymes, and renal function:
• neutrophil count > 1.5 x 10^6/mL
• WBC = 3000/µL
• Platelet count = 100 x 10^9/L (>100,000 per mm^3)
• hemoglobin = 9 g/dL
• INR = 1.5 and PTT = 1.5 x ULN during the last 7 days before therapy
• AST (SGOT)/ALT (SGPT) < 3 x institutional upper limit of normal (5 x lower limit in case of liver metastases)
• bilirubin < 1.5 x ULN
• Serum Creatinine = 1.5 x institutional ULN or creatinine clearance (CrCl) = 30 mL/min (if using the Cockcroft-Gault formula below):
Female CrCl = ((140 - age in years) x weight in kg x 0.85)/(72 x serum creatinine in mg/dL)
Male CrCl = ((140 - age in years) x weight in kg x 1.00)/(72 x serum creatinine in mg/dL)
9. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational products (nivolumab, ipilimumab). Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile) as well as azoospermic men do not require contraception).
10. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 75

Exclusion Criteria

Methodological criteria:
1. Patients <65 years of age
2. Frail patients (DAFI score = 0.35)
3. Esophageal adenocarcinomas, neuroendocrine tumors
4. Prior therapy with an anti-Programmed cell death protein 1 (anti-PD-1), anti-PD-L1, anti-Programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand, a member of the Tumor Necrosis Factor Receptor [TNFR] family), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
5. Participation in another clinical study with an investigational product during the last 30 days before inclusion or 7 half-lifes of previously used trial medication, whichever is longer
6. Previous treatment in the present study (does not include screening failure).
Medical:
7. Any condition or comorbidity that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results, including but not limited to:
a) Major surgery = 28 days prior first dose of study treatment
b) Anticancer treatment during the last 30 days prior to start of nivolumab monotherapy treatment, including systemic therapy, or major surgery [palliative radiotherapy has to be completed at least 2 weeks prior to start of study treatment]
c) history of interstitial lung disease
d) known acute or chronic pancreatitis
e) known active HBV, HCV or HIV infection
f) active tuberculosis
g) any other active infection (viral, fungal or bacterial) requiring systemic therapy
h) history of allogeneic tissue/solid organ transplant
i) diagnosis of immunodeficiency or patient is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of nivolumab-monotherapy treatment.
j) Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
k) Live vaccine within 30 days prior to the first dose of nivolumab-monotherapy treatment or during study treatment.
l) Other clinically significant active malignancy requiring treatment OR less then 5 years disease free interval of another primary malignancy
m) Clinically significant or symptomatic cardiovascular/cerebrovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) within 6 months before enrollment
n) History or clinical evidence of CNS metastases
Exceptions are: Subjects who have completed local therapy and who meet both of the following criteria:
i. are asymptomatic and
ii. have no requirement for steroids 6 weeks prior to start of nivolumab-monotherapy treament. Screening with CNS imaging (CT or MRI) is required only if clinically indicated or if the subject has a history of CNS metastases
Drug related criteria:
8. Medication that is known to interfere with any of the agents applied in the trial.
9. Has known hypersensitivity to nivolumab or ipilimumab or any of the constituents of the products.
10. Any other efficacious cancer treatment except protocol specified treatment at study start.
11. Patient has received any other investigational product within 28 days of study entry.
Safety criteria:
12. Patient has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has n

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of this trial is to demonstrate a significant survival benefit of the combination therapy with nivolumab/ipilimumab treatment in advanced esophageal squamous cell cancer compared to historical data of standard chemotherapy regimens.<br>Additionally, tolerability of nivolumab as single agent and in combination with ipilimumab will be investigated in terms of quality of life. Hence, a key secondary endpoint ‘time to QoL deterioration’ will be implemented.<br><br>;Secondary Objective: Secondary objectives of this study are:<br>• to assess additional efficacy and safety parameters of an intensified immunotherapy regimen.<br>• to assess and explore the predictive value of structured geriatric assessments for treatment-emergent toxicities and treatment discontinuation<br>;Primary end point(s): • Overall survival;Timepoint(s) of evaluation of this end point: End of Study (EoS)

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Key secondary endpoint:<br>• Time to QoL deterioration defined as a loss of = 10 points in the EORTC QLQ-C30 compared to base-line<br>Additional secondary endpoints:<br>• PFS <br>• ORR according to RECIST 1.1 and immune related response criteria (modified RECIST)<br>• Duration of Response (DOR)<br>• Duration of treatment<br>• cumulative dose intensity<br>• QoL (EORTC QLQC30 and ELD14)<br>• AEs/SAEs<br>Geriatric assessments:<br>• Evaluation of the predictive value of the GA containing tests (DAFI, G8-Questionaire etc.) for the occurrence of = grade 3 toxicities.<br>• Predictive value of the assessed geriatric tests for treatment discontinuation;Timepoint(s) of evaluation of this end point: End of Study (EoS)