MelanomaPhase 1/2NCT02736123
Neoadjuvant Combination Biotherapy With Ipilimumab and Nivolumab or Nivolumab Alone
A Phase 1/2 study testing Nivolumab - Arm A and Nivolumab + Ipilimumab - Arm B in people with Melanoma, run by University of Pittsburgh at 1 site in United States.
Trial summary
This study plans to test the pathologic complete response (pCR) rate of the combination biotherapy regimen consisting of nivolumab plus ipilimumab versus nivolumab alone in patients with advanced but operable melanoma. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma
- What is being tested?
- Nivolumab - Arm A and Nivolumab + Ipilimumab - Arm B
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2016to 9 Feb 2017
- Phase
- Phase 1/2
- 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Men and women at least 18 years of age
- Willing and able to give written informed consent
- Performance status Eastern Cooperative Oncology Group (ECOG) zero or 1
- Histologic diagnosis of melanoma belonging to the following AJCC Tumor Node and Metastasis (TNM) stages: Tx or T1-4 and N1b or N2 or N2c or N3 and/or M0 or M1 (if considered surgically operable)
- Patients are eligible for this trial either at presentation for primary melanoma with concurrent regional nodal and/or in-transit metastasis and/or distant metastasis, or at the time of clinically detected nodal and/or in-transit recurrence and/or distant metastasis and may belong to any of the following groups: Primary melanoma with clinically apparent (overt) regional lymph node metastases.
- Clinically detected recurrence of melanoma at the proximal regional lymph node(s) basin.
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- Clinically detected primary melanoma involving multiple regional nodal groups.
- Clinically detected site of nodal metastatic melanoma arising from an unknown primary.
- Patients with intransit or satellite metastases with or without lymph node involvement are allowed if they are considered surgically resectable at baseline.
- Patients with distant metastases with or without intransit or lymph node involvement are allowed if they are considered potentially surgically resectable at baseline. NOTE: All patients must be determined to be surgically resectable at baseline to be eligible for this neoadjuvant study.
- Have measurable disease based on RECIST 1.1.
- Have provided tumor tissue from a newly obtained core, punch, incisional or excisional tumor biopsy. Patients must undergo biopsy (core, punch) or open incisional/excisional biopsy (if done as part of a clinically indicated baseline diagnostic procedure) within 4 weeks of registration on the study.
- Patients must have been evaluated by standard-of-care full body imaging studies (CT, PET/CT or MRI) as part of the initial clinical work-up at baseline (no more than 4 weeks prior to study enrollment) and after completion of induction nivolumab-ipilimumab or nivolumab alone (at 6-8 weeks after the first dose of induction and prior to the definitive surgery procedure).
- Required values for initial laboratory tests:
- White blood cell (WBC) 3000/uL
- Absolute neutrophil count (ANC) 1500/uL
- Platelets 100 x 103/uL
- Hemoglobin 10 g/dL
- Aspartate transaminase/alanine transaminase (AST/ALT) 2.5 x unique learner number (ULN)
- Bilirubin 1.5 ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
- Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 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
- No active or chronic infection with HIV, Hepatitis B, or Hepatitis C
Who cannot join
- Subject will be excluded from participating in the trial if they meet any of the following criteria:
- Patients are excluded if they have a history of central nervous system (CNS)metastases.
- Patients who have had a history of acute diverticulitis, intra-abdominal abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation.
- Any other malignancy from which the patient has been disease-free for less than 3 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix.
- Patients will be excluded if they have an active, known or suspected autoimmune disease. Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded from this study, as are patients with a history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis e.g., Wegener's Granulomatosis); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome).
- Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
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- Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
- Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
- As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen.
- Has an active infection requiring systemic therapy.
- Has received a live vaccine within 30 days prior to the first dose of trial treatment.
- Any underlying medical or psychiatric condition, which in the opinion of the Investigator/Sub-Investigator will make the administration of ipilimumab or nivolumab hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea.
- Patients with underlying heart conditions who are deemed ineligible for surgery by cardiology consult.
- A history of prior treatment with ipilimumab, nivolumab or other cytotoxic T-lymphocyte-associated protein (CTLA-4), progressive disease (PD1) or PD-L1 inhibitor.
- Prior treatment with interferon alfa is allowed.
- A history of prior radiotherapy, chemotherapy, including infusion or perfusion therapy for current disease or any immunotherapy including tumor vaccines, interferon-alfa, interleukins, levamisole or other biologic response modifiers within the past 4 weeks.
- Concomitant therapy with any of the following: IL 2 or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids; unless discontinued ≥ 4 weeks. A history of occasional use of steroid inhalers is allowed.
- Women of childbearing potential (WOCBP), defined above in Section 3.3, who are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 23 weeks after cessation of study drug, or have a positive pregnancy test at baseline, or are pregnant or breastfeeding.
- Melanoma of Uveal Origin
Trial locations and contacts
1 site in 1 country.
United States1 site
UPMC Cancer Center Hillman Cancer Center
Pittsburgh, Pennsylvania, 15232
About this study
Official title: Neoadjuvant Combination Biotherapy With Ipilimumab and Nivolumab or Nivolumab Alone in Patients With Locally/Regionally Advanced/Recurrent Melanoma: A Randomized Efficacy, Safety and Biomarker Study
This study plans to test the pathologic complete response (pCR) rate of the combination biotherapy regimen consisting of nivolumab plus ipilimumab versus nivolumab alone in patients with advanced but operable melanoma. Evaluation of the presence of tumor-infiltrating CD8+ T cells as well as that of PDL1 expression and IDO expression will be associated with clinical response (pathologic and/or radiologic). The study will test the radiologic/clinical preoperative response rate, recurrence free survival (RFS) and overall survival (OS). It will evaluate the safety of neoadjuvant nivolumab and neoadjuvant nivolumab-ipilimumab. Up to 66 patients will be randomized in 1:1 ratio.
Read the detailed description
The study has 2 study arms:
- Nivolumab alone (Arm A)
- Induction phase: nivolumab 3 mg/kg IV infusion every 2 weeks x3 doses. Followed by Definitive Surgery.
- Maintenance phase: nivolumab 3 mg/kg IV infusion every 3 weeks for up to one year from study treatment initiation.
- Ipilimumab + nivolumab (Arm B)
- Induction phase: Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV every 3 weeks x2. Followed by Definitive Surgery.
- Maintenance phase: nivolumab 3 mg/kg IV infusion every 2 weeks for up to one year from study treatment initiation.
Definitive Surgery consists of complete lymph node dissection/ lymphatic, cutaneous, subcutaneous or other distant disease resection (week 6-8+).
- Conditions
- Melanoma
- Being tested
- Nivolumab - Arm A, Nivolumab + Ipilimumab - Arm B
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nivolumab - Arm ADrug
Nivolumab will be given during the induction phase of the study for 6 weeks. This is followed by surgery. Then maintenance therapy (after recovery from surgery).
Nivolumab + Ipilimumab - Arm BDrug
Nivolumab + ipilimumab during the induction phase of the study for 6 weeks. This is followed by surgery (week 6-8+). Then maintenance therapy will be initiated for up to one year from study drug initial administration ((after recovery from surgery).
| Study group | Role | What they receive |
|---|---|---|
| Arm A consists of 3 phases or steps | Experimental | Induction Phase Nivolumab 3 mg/kg IV infusion every 2 weeks for 3 doses
Definitive Surgery Complete lymph node dissection/ lymphatic, cutaneous, subcutaneous disease resection (week 6-8+)
Maintenance Phase (after recovery from surgery) Nivolumab 3 mg/kg IV infusion every 3 weeks Receives: Drug: Nivolumab - Arm A |
| Arm B consists of 3 phases or steps | Experimental | Nivolumab 1 mg/kg IV infusion every 3 weeks for 2 doses given concurrently with Ipilimumab 3 mg/kg IV infusion every 3 weeks for 2 doses
Definitive Surgery Complete lymph node dissection/ lymphatic, cutaneous, subcutaneous disease resection (week 6-8+)
Maintenance Phase (after recovery from surgery) Nivolumab 1 mg/kg IV infusion every 3 weeks for 2 doses given concurrently with Ipilimumab 3 mg/kg IV infusion every 3 weeks for 2 doses; then, Nivolumab 3 mg/kg IV infusion every 3 weeks Receives: Drug: Nivolumab + Ipilimumab - Arm B |
What is being measured
The primary outcome is the main question the study is designed to answer.
Assess the pathologic complete response rate (absence of viable tumor on histologic assessment)
Measured: 5 years
Secondary outcomes (5)
Evaluate preoperative clinical/radiologic response rate
Measured: 5 years
Assess progression free survival
Measured: 5 years
Assess overall survival
Measured: 5 years
Assess biomarkers CD8 T cell, PD-L1 and IDO expression by immunohistochemistry
Measured: 5 years
Assess safety and adverse events
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Apr 2016 (estimated)
- Study startOct 2016
- Primary completion9 Feb 2017
- Study completion9 Feb 2017
Why it stopped: PI is closing the trial as he will be leaving the University of Pittsburgh Medical Center
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for MelanomaStudies of the same condition, open and under way.
- More trials run by University of PittsburghThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Pittsburgh
- Sponsor type
- University, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Responsible party
- Principal investigator, Ahmad Tarhini, University of Pittsburgh
- Investigators
- Ahmad Tarhini, MD, PhD, Principal investigator, University of Pittsburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02736123
- Sponsor's protocol ID
- 15-113
- Status last verified
- Sep 2017
- First submitted
- 28 Mar 2016
- Last updated
- 20 Sep 2017
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 36648215
Study at a glance
From the registry record, last updated by the sponsor on 20 Sep 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neoadjuvant Combination Biotherapy With Ipilimumab and Nivolumab or Nivolumab Alone in Patients With Locally/Regionally Advanced/Recurrent Melanoma: A Randomized Efficacy, Safety and Biomarker Study
- ClinicalTrials.gov ID
- NCT02736123
- Acronym / sponsor ID
- 15-113
- Conditions
- Melanoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: PI is closing the trial as he will be leaving the University of Pittsburgh Medical Center
- Enrolment
- 0 participants (actual)
- Lead sponsor
- University of PittsburghUniversity, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Study start
- Oct 2016
- Primary completion
- 9 Feb 2017 (actual)
- Study completion
- 9 Feb 2017 (actual)
- First posted
- 13 Apr 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study plans to test the pathologic complete response (pCR) rate of the combination biotherapy regimen consisting of nivolumab plus ipilimumab versus nivolumab alone in patients with advanced but operable melanoma. Evaluation of the presence of tumor-infiltrating CD8+ T cells as well as that of PDL1 expression and IDO expression will be associated with clinical response (pathologic and/or radiologic). The study will test the radiologic/clinical preoperative response rate, recurrence free survival (RFS) and overall survival (OS). It will evaluate the safety of neoadjuvant nivolumab and neoadjuvant nivolumab-ipilimumab. Up to 66 patients will be randomized in 1:1 ratio.
Detailed description
The study has 2 study arms:
- Nivolumab alone (Arm A)
- Induction phase: nivolumab 3 mg/kg IV infusion every 2 weeks x3 doses. Followed by Definitive Surgery.
- Maintenance phase: nivolumab 3 mg/kg IV infusion every 3 weeks for up to one year from study treatment initiation.
- Ipilimumab + nivolumab (Arm B)
- Induction phase: Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV every 3 weeks x2. Followed by Definitive Surgery.
- Maintenance phase: nivolumab 3 mg/kg IV infusion every 2 weeks for up to one year from study treatment initiation.
Definitive Surgery consists of complete lymph node dissection/ lymphatic, cutaneous, subcutaneous or other distant disease resection (week 6-8+).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm A consists of 3 phases or steps | Experimental | Drug: Nivolumab - Arm AInduction Phase Nivolumab 3 mg/kg IV infusion every 2 weeks for 3 doses Definitive Surgery Complete lymph node dissection/ lymphatic, cutaneous, subcutaneous disease resection (week 6-8+) Maintenance Phase (after recovery from surgery) Nivolumab 3 mg/kg IV infusion every 3 weeks |
| Arm B consists of 3 phases or steps | Experimental | Drug: Nivolumab + Ipilimumab - Arm BNivolumab 1 mg/kg IV infusion every 3 weeks for 2 doses given concurrently with Ipilimumab 3 mg/kg IV infusion every 3 weeks for 2 doses Definitive Surgery Complete lymph node dissection/ lymphatic, cutaneous, subcutaneous disease resection (week 6-8+) Maintenance Phase (after recovery from surgery) Nivolumab 1 mg/kg IV infusion every 3 weeks for 2 doses given concurrently with Ipilimumab 3 mg/kg IV infusion every 3 weeks for 2 doses; then, Nivolumab 3 mg/kg IV infusion every 3 weeks |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- Men and women at least 18 years of age
- Willing and able to give written informed consent
- Performance status Eastern Cooperative Oncology Group (ECOG) zero or 1
- Histologic diagnosis of melanoma belonging to the following AJCC Tumor Node and Metastasis (TNM) stages: Tx or T1-4 and N1b or N2 or N2c or N3 and/or M0 or M1 (if considered surgically operable)
- Patients are eligible for this trial either at presentation for primary melanoma with concurrent regional nodal and/or in-transit metastasis and/or distant metastasis, or at the time of clinically detected nodal and/or in-transit recurrence and/or distant metastasis and may belong to any of the following groups: Primary melanoma with clinically apparent (overt) regional lymph node metastases.
Key exclusion criteria (19 listed)
- Subject will be excluded from participating in the trial if they meet any of the following criteria:
- Patients are excluded if they have a history of central nervous system (CNS)metastases.
- Patients who have had a history of acute diverticulitis, intra-abdominal abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation.
- Any other malignancy from which the patient has been disease-free for less than 3 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix.
- Patients will be excluded if they have an active, known or suspected autoimmune disease. Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded from this study, as are patients with a history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis e.g., Wegener's Granulomatosis); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nivolumab - Arm ANivolumab will be given during the induction phase of the study for 6 weeks. This is followed by surgery. Then maintenance therapy (after recovery from surgery). | Drug | Arm A consists of 3 phases or steps |
| Nivolumab + Ipilimumab - Arm BNivolumab + ipilimumab during the induction phase of the study for 6 weeks. This is followed by surgery (week 6-8+). Then maintenance therapy will be initiated for up to one year from study drug initial administration ((after recovery from surgery). | Drug | Arm B consists of 3 phases or steps |
Primary outcome
Assess the pathologic complete response rate (absence of viable tumor on histologic assessment)
Time frame: 5 years
5 secondary outcomes
Evaluate preoperative clinical/radiologic response rate
Time frame: 5 years
Assess progression free survival
Time frame: 5 years
Assess overall survival
Time frame: 5 years
Assess biomarkers CD8 T cell, PD-L1 and IDO expression by immunohistochemistry
Time frame: 5 years
Assess safety and adverse events
Time frame: 5 years
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Sep 2017.
- Derived from this study: PubMed 36648215Gorry 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ahmad Tarhini, MD, PhD principal investigator
University of Pittsburgh
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Nivolumab - Arm A and Nivolumab + Ipilimumab - Arm B in people with Melanoma, run by University of Pittsburgh at 1 site in United States.
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 19 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: withdrawn, as of the sponsor's last update on 20 Sep 2017. 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 United States. 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 combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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 was withdrawn before enrolling participants, so there are no results.
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?
Assess the pathologic complete response rate (absence of viable tumor on histologic assessment) (time frame: 5 years). 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 NCT02736123, which also lists 1 linked publication.
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 20 Sep 2017.