Adjuvant Treatment Determined By Pathological Response To Neoadjvuant Nivolumab

NCT04013854 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: UPCC 02619
• Study Type: interventional
• Target: 67
• Locations: 1 country
• Sites: 3

Brief Summary

Subjects with resectable melanoma will receive neoadjuvant nivolumab followed by surgical resection. Post-operatively, subjects will receive open-label treatment with up to 1 year of adjuvant nivolumab or ipilimumab plus nivolumab as determined by pathologic response at the time of resection.

Conditions

Melanoma Stage III; Melanoma

Keywords

nivolumab; ipilimumab; adjuvant; neoadjuvant; surgery

Outcome Measures

Primary Outcomes (1)

• Recurrence-Free Survival

  Recurrence-free survival (RFS) is defined as the time from date of surgery to date of disease recurrence, death due to any cause or most recent follow-up documenting freedom from recurrence (i.e., scan date).

  1 year

Secondary Outcomes (3)

• Frequency and Incidence of Adverse Events

  Up to 13 months

• Pathological Response Rate

  Approximately 4 weeks

• Overall Survival

  Up to 7 Years

Study Arms (3)

Arm A: Adjuvant Nivolumab (Complete Pathological Response)

ACTIVE COMPARATOR

480 mg IV for up to one year

Drug: nivolumab

Arm B: Adjuvant Nivolumab (Less than Complete Response)

ACTIVE COMPARATOR

480 mg IV for up to one year

Drug: nivolumab

Arm C: Adjuvant Combination (Less than Complete Response)

EXPERIMENTAL

ipilimumab (1mg/kg) plus nivolumab (3mg/kg) for 4 doses and then nivolumab (480 mg) alone for a total of one year

Drug: nivolumab; Drug: Ipilimumab

Interventions

nivolumab DRUG

All arms will receive a pre-surgery dose of nivolumab (480 mg IV). Post-surgery nivolumab doses will be determined by pathologic response and randomization.

Arm A: Adjuvant Nivolumab (Complete Pathological Response); Arm B: Adjuvant Nivolumab (Less than Complete Response); Arm C: Adjuvant Combination (Less than Complete Response)

Ipilimumab DRUG

Only subjects who fail to achieve a complete, or near complete, pathological response, and are then randomized to Arm C will receive Ipilimumab (1 mg/kg) )

Arm C: Adjuvant Combination (Less than Complete Response)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The subject must have clinical stage III resectable melanoma per investigator. Subjects may not have a diagnosis of uveal or mucosal melanoma.
• Either the subject or the subject's legally authorized representative must be willing and able to provide written informed consent before the performance of any protocol-related procedures.
• The subject must be ≥18 years of age on day of signing informed consent.
• The subject must have a performance status of 0 or 1 on the ECOG Performance Scale.
• The subject must demonstrate adequate organ function as defined in Table 1; all screening labs must be performed within 28 days of treatment initiation.
• Hematologic System: Absolute neutrophil count (ANC) ≥1500/mcL; Platelets ≥100,000/mcL; Hemoglobin ≥9 g/dL or ≥5.6 mmol/L
• Renal System: Serum creatinine OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥50 mL/min for subject with creatinine levels \>1.5 X institutional ULN
• Hepatic System: Serum total bilirubin ≤1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \>1.5 ULN; AST (SGOT) and ALT (SPGT) ≤2.5 X ULN OR ≤5 X ULN for subjects with liver metastases
• A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: A.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR B.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and is willing to use a highly effective method of contraception or abstain from heterosexual intercourse for at least 2 weeks prior to the time of first dose of study medication through 5 months after the last dose of study medication.
• Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
• Male subjects must agree to follow the contraceptive guidance in Appendix 3 starting with the first dose of study medication, while on study, through 7 months after the last dose of study medication.

You may not qualify if:

• Subject has unresectable disease; i.e. in the opinion of the surgical oncologist, all of the subject's melanoma cannot be completely removed with a clear margin.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137), interferon, high dose IL-2 or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to the first dose of study drug. Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy are an exception to this criterion.
• If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
• Subject has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) within 4 weeks to the first dose of study drug.
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Has a known additional malignancy that is progressing or requires active treatment. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• Has active autoimmune disease that has required systemic treatment in the past 3 months (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has evidence of active interstitial lung disease or a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has an active infection requiring systemic therapy.
• Patients known to be positive for Human Immunodeficiency Virus (HIV) if they have a CD4 count of less than 350 mm3 and a serum HIV viral load \> 25,000 IU/mL
• Has active Hepatitis B infection or active Hepatitis C virus infection as determined by medical record review.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

Sponsors & Collaborators

• Abramson Cancer Center at Penn Medicine: lead

Study Sites (3)

Duke Cancer Institute

Durham, North Carolina, 27710, United States

Location

Lancaster General Hospital

Lancaster, Pennsylvania, 17601, United States

Location

Abramson Cancer Center, University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (4)

• Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbe C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA; CheckMate 238 Collaborators. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. doi: 10.1056/NEJMoa1709030. Epub 2017 Sep 10.

  PMID: 28891423 BACKGROUND

• Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. doi: 10.1056/NEJMoa1802357. Epub 2018 Apr 15.

  PMID: 29658430 BACKGROUND

• Huang AC, Orlowski RJ, Xu X, Mick R, George SM, Yan PK, Manne S, Kraya AA, Wubbenhorst B, Dorfman L, D'Andrea K, Wenz BM, Liu S, Chilukuri L, Kozlov A, Carberry M, Giles L, Kier MW, Quagliarello F, McGettigan S, Kreider K, Annamalai L, Zhao Q, Mogg R, Xu W, Blumenschein WM, Yearley JH, Linette GP, Amaravadi RK, Schuchter LM, Herati RS, Bengsch B, Nathanson KL, Farwell MD, Karakousis GC, Wherry EJ, Mitchell TC. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat Med. 2019 Mar;25(3):454-461. doi: 10.1038/s41591-019-0357-y. Epub 2019 Feb 25.

  PMID: 30804515 BACKGROUND

• Gorry C, McCullagh L, O'Donnell H, Barrett S, Schmitz S, Barry M, Curtin K, Beausang E, Barry R, Coyne I. Neoadjuvant treatment for stage III and IV cutaneous melanoma. Cochrane Database Syst Rev. 2023 Jan 17;1(1):CD012974. doi: 10.1002/14651858.CD012974.pub2.

  PMID: 36648215 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 8, 2019
• First Posted: July 10, 2019
• Study Start: January 1, 2020
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026
• Last Updated: November 6, 2025

Record last verified: 2025-11

Locations

US (3)