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

All Drugs and Chemicals

Antineoplastic Agents

Immunomodulating Agents

Nivolumab

Ipilimumab

Trametinib

Dabrafenib

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

2 cycles of neoadjuvant ipilimumab (80mg) + nivolumab (240mg) every 3 weeks followed by a total lymph node dissection (TLND) and if applicable, resection of in-transit metastases.

Patients with a pathologic partial or non-response in arm A will also receive adjuvant nivolumab 480 mg every 4 weeks 11 cycles. In case of BRAF V600E/K mutation-positivity, patients will be treated with adjuvant dabrafenib plus trametinib for 46 weeks instead.

Standard upfront total lymph node dissection (TLND) and if applicable, resection of in-transit metastases followed by 12 cycles adjuvant nivolumab 480 mg every 4 weeks

2 cycles ipilimumab (80mg) + nivolumab (240mg) every 3 weeks followed by total lymph node dissection

Neoadjuvant ipilimumab + nivolumab

Upfront total lymph node dissection followed by 12 cycles of nivolumab (480mg) every 4 weeks.

Adjuvant nivolumab

Christian Blank, Prof

Georgina Long, Prof

This is an international (Australia, Europe, and USA) open-label two-arm randomized phase 3 trial including 420 stage III (≤3 resectable in-transit metastases allowed) cutaneous or unknown primary melanoma patients. Patients will be randomized 1:1 to receive either 2 cycles of neoadjuvant ipilimumab 80 mg + nivolumab 240 mg every 3 weeks followed by a total lymph node dissection (TLND) and, if applicable, resection of in-transit metastases (arm A) versus standard upfront TLND +/- resection of in-transit metastases followed by 12 cycles adjuvant nivolumab 480 mg every 4 weeks (arm B). Patients with a pathologic partial or non-response in arm A will also receive adjuvant nivolumab 480 mg every 4 weeks for 46 weeks (11 cycles). In case of BRAF V600E/K mutation-positivity, patients from arm A with a pathologic partial or non-response (\>10% viable tumor) will be treated with adjuvant dabrafenib plus trametinib for 46 weeks. Patients will be treated in the study in both arms until melanoma progression to irresectable stage III or stage IV disease, disease recurrence, unacceptable toxicity, subject withdrawal of consent or until end of study treatment.

An interim analysis will be performed after 60 events have occurred. The data safety monitory board (DSMB) will be ad hoc consulted when unexpected toxicities are reported. Patients will be followed by 12 weekly CT scans until end of year 3 and then until year 5 according to the institute's standards.

Open-label two-arm randomized phase 3 trial

Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma

Multicenter Phase 3 Trial Comparing Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma - NADINA

EFS is defined as time from randomization to melanoma progression (irresectable stage III or stage IV disease), melanoma recurrence, treatment-related death, or melanoma-related death, whichever occurs first. Occurrence of a new primary melanoma during treatment/follow-up is also regarded as an event. Presurgical resectable progression to stage III disease in arm A is not defined as an event, even as death to another reason than melanoma or the study treatment.

RFS is defined as time between date of surgery and date of melanoma recurrence, treatment-related death or melanoma-related death, whichever occurs first.

DMFS is defined as time between date of randomization and date of first distant metastasis, treatment-related death or melanoma-related death, whichever occurs first.

OS is defined as time between date of randomization and date of death.

The pathologic response rate will be categorized into pathologic complete response (pCR), near-pCR, major pathologic response (MPR), pathologic partial response (pPR), pathologic no response (pNR), according to International Neoadjuvant Melanoma Consortium (INMC) criteria.

Frequency of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0.

Duration of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0.

Type of all grade and grade 3-5 treatment-related adverse events according to CTCAE 5.0.

Surgical complication rates according to Clavien-Dindo surgical classification.

Quality of life as measured by EORTC Quality of Life Questionnaire-core 30 (QLQ C30). The QLQ-C30 is scored on 4 point Likert-scales: "Not at all", "A little", "Quite a bit", and "Very much." and is composed of both multi-item scales and single-item measures. A high scale score represents a higher response level. Thus 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.

Quality of life as measured by the Melanoma Subscale and Melanoma Surgery Subscale of Functional Assessment of Cancer Therapy - Melanoma (FACT-M). The FACT-M is scored on a 5 point Likert-scale: "Not at all", "A little bit", "Somewhat", "Quite a bit", and "Very much.". A Higher score represents higher Health Related Quality of Life (HRQoL).

Quality of life as measured by the Cancer Worry Scale. The Cancer Worry Scale is scored on a 4 point Likert-scale: "Almost never", "Sometimes", "Often", and "Almost always". Higher scores indicate more worrying about cancer.

Quality of life as measured by the Hospital Anxiety and Depression Scale (HADS) questionnaire. The HADS is a questionnaire that is scored on several 4 point Likert-scales. Higher score on the HADS questionnaire indicates more hospital-related anxiety and depression.

Quality of life as measured by the 5-level EuroQOL-5D questionnaire (EQ-5D-5L).

Quality of life as measured by an immunotherapy-specific questionnaire.

Quality of life as measured by an assessment of work performance.

Quality of life as measured by a questionnaire on sexual health.

Quality of life as measured by the Amsterdam Cognition Scale.

Cost-effectiveness measured by an incremental cost-effectiveness ratio (ICER) (e.g., incremental cost per quality-adjusted life-year (QALY) gained).

Bristol-Myers Squibb

The Netherlands Cancer Institute

Head and Neck Neoplasms

Cisplatin

* Neoadjuvant dose with Nivolumab 3mg/kg after randomization within 2 weeks before surgery
* Surgical resection of primary tumor including neck dissection according to standard of care
* 6-7 weeks risk-adapted adjuvant radio(-chemo)therapy 56-66 Gy (chemotherapy Cisplatin 100 mg/m2 on days 1, 22, 43, or Cisplatin once weekly (40mg/m2) for high risk patients only), start within 6 weeks post-surgery

Arm Ia:

• Adjuvant administration of Nivolumab 3mg/kg i.v. d1 every 2 weeks within 6 weeks after end of radiotherapy until progression or up to 6 months

Arm Ib:

• Adjuvant administration of Nivolumab 3mg/kg i.v. d1 every 2 weeks and Ipilimumab 1mg/kg i.v. d1 every 6 weeks within 6 weeks after end of radiotherapy until progression or up to 6 months

* Surgical resection of primary tumor including neck dissection according to standard of care
* 6-7 weeks risk-adapted adjuvant radio(-chemo)therapy 56-66 Gy (chemotherapy Cisplatin 100 mg/m2 on days 1, 22, 43 or Cisplatin once weekly (40mg/m2) in high risk patients), start within 6 weeks post-surgery
* Standard follow-up

Surgical resection of primary tumor including neck dissection according to standard of care

Surgical resection of primary tumor

Risk-adapted adjuvant radio(-chemo)therapy 56-66 Gy (chemotherapy Cisplatin 100 mg/m2 on days 1, 22, 43, or Cisplatin once weekly (40mg/m2) for high risk patients only)

Adjuvant radio(-chemo)therapy

Neoadjuvant dose with Nivolumab 3mg/kg after randomization within 2 weeks before surgery

Neoadjuvant Nivolumab

Administration of Nivolumab 3mg/kg i.v. d1 every 2 weeks within 6 weeks after end of radiotherapy until progression or up to 6 months

Adjuvant Nivolumab

Administration of Nivolumab 3mg/kg i.v. d1 every 2 weeks and Ipilimumab 1mg/kg i.v. d1 every 6 weeks within 6 weeks after end of radiotherapy until progression or up to 6 months

Adjuvant Nivolumab and Ipilimumab

PD Dr. med. Chia-Jung Busch

Multicenter randomized controlled phase III study of nivolumab alone or in combination with ipilimumab as immunotherapy vs standard follow-up in surgical resectable HNSCC after adjuvant therapy

Surgically treated locally advanced head and neck squamous cell carcinoma often requires postoperative chemoradiation with high risk of acute and late toxicity. DFS after 2 years is approximately 70%. Combining anti-PD-1 and anti-CTLA4 as a maintenance therapy may improve DFS due to anti-tumor effects of immunotherapy by enhancing cross-presentation of tumor antigens.

Arm Ia and Arm Ib are summarized in one Arm, due to central ethics committee, as they both include neoadjuvant and adjuvant treatment compared to Arm II

Study of Nivolumab Alone or in Combination With Ipilimumab as Immunotherapy vs Standard Follow-up in Surgical Resectable HNSCC After Adjuvant Therapy

Multicenter Randomized Controlled Phase III Study of Nivolumab Alone or in Combination With Ipilimumab as Immunotherapy vs Standard Follow-up in Surgical Resectable HNSCC After Adjuvant Therapy

disease free survival (DFS) at 3 years of nivolumab alone or in combination with ipilimumab as adjuvant immunotherapy after adjuvant radio(chemo)therapy in locally advanced resected HNSCC

Disease assessment (CT/ MRI) and Panendoscopy and FFPE in case of suspicion or recurrence

Follow Up- Visits after end of treatment every 3 months until month 36 after randomization, afterwards every 6 months

We compare disease free survival, defined as time from randomization to date of first observed either histologically proven recurrence (local, locoregional or distant), or death from any cause whatever occurs first, of arm Ia to arm II and of arm Ib to arm II

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma	NCT04949113	Malignant Melan...	Neoadjuvant ipi... Adjuvant nivolu...	16 Years -	The Netherlands Cancer Institute
Study of Nivolumab Alone or in Combination With Ipilimumab as Immunotherapy vs Standard Follow-up in Surgical Resectable HNSCC After Adjuvant Therapy	NCT03700905	Head and Neck C...	Surgical resect... Adjuvant radio(... Neoadjuvant Niv... Adjuvant Nivolu... Adjuvant Nivolu...	18 Years -	Universitätsklinikum Hamburg-Eppendorf
Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma	NCT04949113	Malignant Melan...	Neoadjuvant ipi... Adjuvant nivolu...	16 Years -	The Netherlands Cancer Institute

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