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Esophageal CancerPhase 2RAMONANCT03416244

A Multicenter Open-label Phase II Trial to Evaluate Nivolumab and Ipilimumab for 2nd Line Therapy in Elderly Patients With Advanced Esophageal Squamous Cell Cancer

A Phase 2 study testing Nivolumab and Ipilimumab in people with Esophageal Cancer and Oesophageal Cancer, run by AIO-Studien-gGmbH at 1 site in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Cancer - including esophageal squamous cell cancer (ESCC) - is a disease of the elderly but little is known about the biology and progression of cancers in these patients. While most patients receive chemotherapy and/or chemo-radiation as first treatment, no treatment standard for following treatments has been… Read more about this study

Who is it for?
Ages 65 years and older
What is being tested?
Nivolumab and Ipilimumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
66 participants
Where
1 siteGermany
Study dates
21 Feb 2018to 19 Nov 2021
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 65 years and older
  • All sexes
  • No healthy volunteers
  • Older adult

Who may be able to join

  • 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
  • Age ≥ 65 years at time of study entry
  • 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
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  • 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
  • Geriatric status: SlowGo or GoGo according to G8 and DAFI assessment (G8 > 14 points or CGA/DAFI 0.2 < 0.35)
  • At least 1 measurable lesion according to RECIST 1.1
  • Karnofsky performance status ≥ 50
  • Sufficient cardiac functional reserve defined as ejection fraction ≥ 50%
  • 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
  • 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 (i.e., who are postmenopausal or surgically sterile) as well as azoospermic men do not require contraception)
  • 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

Who cannot join

  • Patients < 65 years of age
  • Frail patients (DAFI score ≥ 0.35)
  • Esophageal adenocarcinomas, neuroendocrine tumors
  • 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)
  • 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
  • Previous treatment in the present study (does not include screening failure).
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  • 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:
  • Major surgery ≤ 28 days prior first dose of study treatment
  • 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]
  • History of interstitial lung disease
  • Known acute or chronic pancreatitis
  • Known active HBV, HCV or HIV infection
  • Active tuberculosis
  • Any other active infection (viral, fungal or bacterial) requiring systemic therapy
  • History of allogeneic tissue/solid organ transplant
  • 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.
  • 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. Exceptions: Subjects with vitiligo, hypothyroidism, diabetes mellitus type I or resolved childhood asthma/atopy are an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with Hashimoto thyroiditis, hypothyroidism stable on hormone replacement or psoriasis not requiring treatment are not excluded from the study.
  • Live vaccine within 30 days prior to the first dose of Nivolumab monotherapy treatment or during study treatment.
  • Other clinically significant active malignancy requiring treatment OR less then 5 years disease free interval of another primary malignancy
  • 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
  • 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 treatment. Screening with CNS imaging (CT or MRI) is required only if clinically indicated or if the subject has a history of CNS metastases
  • Medication that is known to interfere with any of the agents applied in the trial
  • Has known hypersensitivity to Nivolumab or Ipilimumab or any of the constituents of the products
  • Any other efficacious cancer treatment except protocol specified treatment at study start
  • Patient has received any other investigational product within 28 days of study entry
  • Patient has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. [Subjects with ≤ Grade 2 neuropathy or alopecia are an exception to this criterion and may qualify for the study.]
  • Female subjects who are pregnant, breast-feeding or male/female patients of reproductive potential who are not employing an effective method of birth control (failure rate of less than 1% per year). [Acceptable methods of contraception are: implants, injectable contraceptives, combined oral contraceptives, intrauterine pessaries (only hormonal devices), sexual abstinence or vasectomy of the partner]. Women of childbearing potential must have a negative pregnancy test (serum β-HCG) at screening.
  • Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.
  • Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
  • Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].

Trial locations and contacts

1 site in 1 country.

Germany1 site

  • Universitätsmedizin Mannheim, Heidelberg University, II. Medizinische Klinik

    Mannheim, 68167

Other trials in Germany

About this study

Cancer - including esophageal squamous cell cancer (ESCC) - is a disease of the elderly but little is known about the biology and progression of cancers in these patients.

While most patients receive chemotherapy and/or chemo-radiation as first treatment, no treatment standard for following treatments has been established so far and there is a clear unmet medical need, especially for elderly patients.

Hence, this study assesses the efficacy and safety of two experimental immunotherapy regimens (Nivolumab monotherapy or Nivolumab/Ipilimumab combination) in elderly patients with advanced esophageal squamous cell cancer.

Read the detailed description

Cancer - including esophageal squamous cell cancer (ESCC) - is a disease of the elderly, more than 60% of all tumors arise in patients with the age of 65 years or older. In contrast, little is known about the biology and progression of cancers in these patients, since most clinical trials enroll patients with age limits of 70 or 75 years.

While most patients undergo chemotherapy and/or chemo-radiation in first-line, the role of second-line therapy is less well understood. No treatment standard has been established so far and there is a clear unmet medical need. This is particularly true for geriatric patients for whom palliative systemic therapies are especially challenging.

Hence, the primary objective of this trial is to demonstrate a significant survival benefit of two experimental immunotherapy regimens (Nivolumab monotherapy or Nivolumab/Ipilimumab combination) in elderly patients with advanced esophageal squamous cell cancer compared to historical data of standard chemotherapy regimens.

Being tested
Nivolumab, Ipilimumab
Medical subject headings
Esophageal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NivolumabDrug

    Nivolumab 240 mg IV fixed dose every two weeks

  • IpilimumabDrug

    Ipilimumab 1mg/kg IV every six weeks (starting in week 7 after safety assessment)

Study groups in NCT03416244
Study groupRoleWhat they receive
A: Nivolumab / Ipilimumab combination treatmentExperimentalNivolumab 240 mg fixed dose IV every 2 weeks; Additionally, after 7 week safety assessment Ipilimumab 1mg/kg IV every 6 weeks
Receives: Drug: Nivolumab; Drug: Ipilimumab
B. Nivolumab monotherapyExperimentalNivolumab 240 mg fixed dose IV every 2 weeks
Receives: Drug: Nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall survival

    OS measured from first dose of 2nd line therapy to the date of death

    Measured: 36 months

Secondary outcomes (9)

  1. Time to QoL deterioration

    Time to QoL deterioration defined as a loss of ≥ 10 points in the EORTC QLQ-C30 compared to base-line

    Measured: 36 months

  2. Progression free survival

    Time from first dosing date to the date of the first documented tumor progression

    Measured: 36 months

  3. Objective Response rate

    Proportion of treated subjects with response from baseline

    Measured: 36 months

  4. Duration of response

    Time from first confirmed response to the date of the documented progressive disease or death

    Measured: 36 months

  5. Duration of treatment

    Time from date of first dose of Nivolumab monotherapy until permanent discontinuation of either NIVO mono therapy or NIVO/IPI combination treatment.

    Measured: 36 months

  6. Cumulative dose intensity

    Cumulative dose for each IMP

    Measured: 36 months

  7. Quality of Life C30

    EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer - Quality of Life Core Questionnaire (30 items) Version 3.0. The QLQ-C30 is composed of multi-item scales and single-item measures, including five functional scales, three symptom scales, a global health status / QoL scale, and six single items.

    All of the scales and single-item measures have a score range from 0 to 100. A high score shows a high response level. A high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems

    Measured: 36 months

  8. Quality of Life ELD14

    EORTC QLQ-ELD14 (European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire Module for elderly Cancer patients (14 items), comprising five multi-item and two single-item subscales. The multi-item subscales include questions about mobility (3 items), worries about others (2 items), worries (3 items), maintaining purpose (2 items), and burden of illness (2 items). The single-item subscales include questions related to joint stiffness and Family support. Items are assessed on a 4-level numerical scale with 1= "not at all", 2= "a little", 3= "quite a bit", and 4= "very much". Scores are linearly converted and summated into a scaled score from 0 to 100, with a higher score representing a worse QOL or better QOL for purpose and family support.

    Measured: 36 months

  9. Incidence of Treatment-Emergent Adverse Events

    AE/SAE evaluation

    Measured: 36 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Jan 2018
  2. Study start21 Feb 2018
  3. Primary completion19 Nov 2021
  4. Study completion19 Nov 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
66 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03416244
Sponsor's protocol ID
AIO-STO-0117
Other IDs
2017-002056-86, CA209-9DD, 2017
Acronym
RAMONA
Status last verified
Sep 2022
First submitted
24 Jan 2018
Last updated
29 Sep 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Li M, Meindl-Beinker NM, Maenz M, Betge J, Schulte N, Zhan T, Hofheinz RD, Vogel A, Angermeier S, Bolling C, de Wit M, Jakobs R, Karthaus M, Stocker G, Thuss-Patience P, Leidig T, Bauer H, Ebert MP, Haertel N. Functional status and quality of life in older patients with advanced esophageal squamous cell cancer receiving second-line nivolumab +/- ipilimumab therapy: A post hoc analysis of the phase 2, multicenter RAMONA study. J Geriatr Oncol. 2024 Sep;15(7):101838. doi: 10.1016/j.jgo.2024.101838. Epub 2024 Aug 3.

    PubMed 39097500

  • Ebert MP, Meindl-Beinker NM, Gutting T, Maenz M, Betge J, Schulte N, Zhan T, Weidner P, Burgermeister E, Hofheinz R, Vogel A, Angermeier S, Bolling C, de Wit M, Jakobs R, Karthaus M, Stocker G, Thuss-Patience P, Leidig T, Gaiser T, Kather JN, Haertel N. Second-line therapy with nivolumab plus ipilimumab for older patients with oesophageal squamous cell cancer (RAMONA): a multicentre, open-label phase 2 trial. Lancet Healthy Longev. 2022 Jun;3(6):e417-e427. doi: 10.1016/S2666-7568(22)00116-7. Epub 2022 Jun 9.

    PubMed 36098320

  • Meindl-Beinker NM, Betge J, Gutting T, Burgermeister E, Belle S, Zhan T, Schulte N, Maenz M, Ebert MP, Haertel N. A multicenter open-label phase II trial to evaluate nivolumab and ipilimumab for 2nd line therapy in elderly patients with advanced esophageal squamous cell cancer (RAMONA). BMC Cancer. 2019 Mar 14;19(1):231. doi: 10.1186/s12885-019-5446-2.

    PubMed 30871493

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Nivolumab and Ipilimumab in people with Esophageal Cancer and Oesophageal Cancer, run by AIO-Studien-gGmbH at 1 site in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 29 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall survival (time frame: 36 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03416244, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Sep 2022.

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