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Refractory Cutaneous MelanomaPhase 2NCT05200143

Study of Ipilimumab, Nivolumab, and Cabozantinib in Patients With Cutaneous Melanoma

A Phase 2 study testing Ipilimumab, Nivolumab and Cabozantinib in people with Refractory Cutaneous Melanoma, run by Providence Health & Services at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

The primary objective of this clinical trial is to evaluate the clinical efficacy and progression free survival of the triplet combination of ipilimumab + nivolumab + cabozantinib in patients with anti-PD-1/PD-L1 refractory metastatic cutaneous melanoma. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Refractory Cutaneous Melanoma
What is being tested?
Ipilimumab, Nivolumab and Cabozantinib
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
4 participants
Where
1 siteUnited States
Study dates
8 Jun 2022to 23 Jul 2024
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

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

  • Histologically (or cytologically) confirmed diagnosis of metastatic cutaneous melanoma.
  • Prior therapy:
  • Must have been treated previously with an immune checkpoint inhibitor targeting PD-1 or PD-L1.
  • Disease progression following treatment with prior anti-PD-1/PD-L1 therapy must be confirmed at least 4 weeks after the first imaging showing disease progression to rule out pseudoprogression.
  • Prior therapy with BRAF/MEK inhibitors (before or after anti-PD-1(L1) therapy) is allowed but not required.
  • Patients who develop unresectable/metastatic disease while receiving or following completion of adjuvant systemic anti-PD-1/PD-L1 therapy are eligible.
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  • Recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
  • Men and women, aged ≥ 18 years
  • Measurable disease meeting the following iRECIST criteria:
  • At least 1 lesion of ≥1.0 cm in the longest diameter for a non-lymph node or >1.5 cm in the short-axis diameter for a lymph node metastasis that is serially measurable according to iRECIST using computed tomography/magnetic resonance imaging (CT/MRI).
  • Lesions that have had external beam radiotherapy must show evidence of disease progression to qualify as a target lesion.
  • ECOG performance status ≤ 1
  • Adequate cardiac function, as defined by:
  • Left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram,
  • Baseline QTc interval ≤ 480 ms
  • Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 14 days before first dose of study treatment:
  • Absolute neutrophil count (ANC) ≥ 1500/µL without granulocyte colony-stimulating factor support.
  • White blood cell count ≥ 2500/µL.
  • Platelets ≥ 100, 000/µL without transfusion.
  • Hemoglobin ≥ 9 g/dL (≥ 90 g/L).
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3x upper limit of normal (ULN). ALP ≤ 5x ULN with documented bone metastases.
  • Total bilirubin < 1.5 x ULN. Note: Individuals who have a total bilirubin level >1.5 X ULN will be allowed if their indirect bilirubin level is < 1.5 x ULN (i.e., participants with suspected or known diagnosis of Gilbert's Syndrome)
  • Serum albumin ≥ 2.8 g/dl.
  • (PT)/INR or partial thromboplastin time (PTT) test < 1.3x the laboratory ULN
  • Serum creatinine ≤ 1.5x ULN or calculated creatinine clearance ≥ 40mL/min (≥ 0.675mL/sec) using the Cockcroft-Gault equation:
  • Males: (140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72) Females: [(140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85
  • Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-h urine protein ≤ 1 g.
  • Capable of understanding and complying with the protocol requirements and must have signed the informed consent document.
  • Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of cabozantinib and 3 months after the last dose of ipilimumab and 5 months after the last dose of nivolumab.
  • Participants of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) at screening, within 24 hours prior to receiving the first dose of study medication, and then every 4 weeks while on treatment.
  • Participants of child-bearing potential agree to use highly effective methods of contraception starting with the first dose of assigned study intervention through 5 months after the last dose of study therapy. Participants of childbearing potential are those who are not proven postmenopausal. Postmenopausal is defined as any of the following:
  • Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
  • Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post-menopausal range for women under 50
  • Radiation-induced oophorectomy with last menses >1 year ago
  • Chemotherapy-induced menopause with >1 year interval since last menses
  • Surgical sterilisation (bilateral oophorectomy or hysterectomy

Who cannot join

  • Prior therapy:
  • Prior systemic therapy within 2 weeks of cycle 1 day 1
  • Prior therapy with a VEGF(R) inhibitor alone or in combination with immune checkpoint inhibitor(s).
  • Prior therapy with an anti-CTLA-4 antibody
  • Participants with active, known, or suspected autoimmune disease. Participants with type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll.
  • Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids are permitted in the absence of active autoimmune disease.
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  • History of allergy or hypersensitivity to any monoclonal antibody
  • Previous or concurrent malignancy within 3 years of study entry, with the following exceptions:
  • adequately treated basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy; OR
  • other solid tumors treated curatively in which the expected rate of recurrence within 5 years is < 5%.
  • Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
  • History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) <6 months prior to screening,
  • Symptomatic congestive heart failure (i.e. Grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality <6 months prior to screening. Exceptions include asymptomatic/well-controlled atrial fibrillation/flutter or paroxysmal supraventricular tachycardia;
  • Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, despite medical therapy
  • History of thromboembolic or cerebrovascular events ≤ 6 months prior to the first dose of study treatment. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e., massive or sub-massive) deep vein thrombosis or pulmonary emboli.
  • Note: Individuals with either deep vein thrombosis or pulmonary emboli that does not result in hemodynamic instability are allowed to enroll as long as they are on a stable dose of anticoagulants for at least 4 weeks.
  • Note: Individuals with thromboembolic events related to indwelling catheters or other procedures may be enrolled.
  • Known positive serology for HIV (Human immunodeficiency virus), active hepatitis B, and/or active hepatitis C infection
  • Impaired gastrointestinal function or disease that may significantly alter the absorption of cabozantinib (e.g., uncontrolled vomiting or malabsorption syndrome)
  • Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
  • Any other condition that would, in the Investigator's judgment, contraindicate an individual's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc.
  • Participants who have undergone major surgery (e.g., intracranial, intrathoracic, or intra-abdominal surgery) ≤ 3 weeks prior to starting study drug, minor surgery < 10 days prior to starting study drug or who have not recovered from side effects of such procedure. Subjects must have complete wound healing from major surgery or minor surgery before first dose of study treatment.
  • Participants that are pregnant or nursing (lactating)
  • Prisoners or individuals who are involuntarily incarcerated
  • Medical, psychiatric, cognitive or other conditions that may compromise the participant's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study
  • Patients with leptomeningeal involvement by melanoma
  • Participants with CNS metastases or leptomeningeal carcinomatosis are not eligible unless:
  • CNS metastases have been treated and remained stable by radiographic evaluation at least 4 weeks after CNS directed therapy and/or:
  • There are ≤5 asymptomatic untreated CNS metastases measuring no larger than 10 mm each.
  • Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment."
  • Radiation therapy for bone metastases within 2 weeks, any other radiation therapy within 4 weeks, or systemic treatment with radionuclides within 6 weeks before first dose of study treatment; ongoing clinically relevant complications from prior radiation therapy are not eligible
  • Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:
  • Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
  • Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.
  • Administration of a live, attenuated vaccine within 30 days prior to first dose of study treatment
  • Evidence of tumor invading the GI tract, active peptic ulcer disease, IBD, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of pancreatic duct or common bile duct, or gastric outlet obstruction
  • Abdominal fistula, GI perforation, bowel obstruction or intra-abdominal abscess within 6 months before first dose of study treatment. Complete healing of intra-abdominal abscess must be confirmed before first dose of study treatment
  • Clinically significant hematuria, hematemesis, or hemoptysis of >0.5 tsp (2.5ml) of red blood, or other history of significant bleeding within 12 weeks before first dose of study treatment
  • Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation
  • Lesions invading or encasing any major blood vessels.
  • History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
  • Serious non-healing wound/ulcer/bone fracture.
  • Moderate to severe hepatic impairment (Child-Pugh B or C).
  • Requirement for hemodialysis or peritoneal dialysis.
  • History of solid organ or allogenic stem cell transplant.
  • QTcF > 500 msec within 14 days before first dose of study treatment (Note: Could also be listed in Inclusion as ≤ 500 msec)

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Providence Portland Medical Center

    Portland, Oregon, 97213

Other trials in United States

About this study

Official title: A Phase II, Single-Arm Clinical Trial Evaluating the Triplet Combination of Ipilimumab, Nivolumab, and Cabozantinib in Patients With Anti-PD-1(L1) Refractory Cutaneous Melanoma

The primary objective of this clinical trial is to evaluate the clinical efficacy and progression free survival of the triplet combination of ipilimumab + nivolumab + cabozantinib in patients with anti-PD-1/PD-L1 refractory metastatic cutaneous melanoma.

Read the detailed description

This is a phase II, single arm, single institution clinical trial. Eligible adults with anti-PD-1 refractory, unresectable/metastatic cutaneous melanoma will be treated with the triplet combination of ipilimumab 1 mg/kg + nivolumab 3 mg/kg every 3 weeks for 4 cycles in addition to cabozantinib 40 mg/day. For cycles 5+, treatment will consist of nivolumab 480 mg IV every 4 weeks in combination with cabozantinib 40 mg/day. The total duration of therapy will be 24 months or until either disease progression or the occurrence of unacceptable drug-related toxicity. Regular tumor assessments should be performed to determine if PD is present.

Keywords
Phase 2, Melanoma, ipilimumab, nivolumab, cabozantinib, anti-pd-1
Medical subject headings
Melanoma

What participants receive

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

  • IpilimumabDrug

    Ipilimumab is a fully human IgG1 kappa monoclonal antibody that binds the co-inhibitory receptor CTLA-4. Antibody binding prevents interaction with the CTLA-4 ligands CD80 and CD86. Blockade of CTLA-4 results in increased T cell activation and proliferation. Ipilimumab was the first immune checkpoint inhibitor to receive FDA approval as a cancer therapy. Treatment of patients with advanced metastatic melanoma with ipilimumab monotherapy resulted in improved overall survival. Subsequent clinical trials with ipilimumab alone and in combination with anti-PD-1 antibodies have demonstrated impressive clinical activity in patients with melanoma, renal cell carcinoma, non-small cell lung cancer and other cancers. Side effects of ipilimumab result from autoimmune attack on healthy tissues. Side effects may include dermatitis, colitis, hepatitis, hypophysitis, pneumonitis, endocrinopathies, nephritis, arthritis, neuropathies and others.

  • NivolumabDrug

    Also called BMS-936558, MDX1106, ONO-4538

    Nivolumab is a fully human IgG4 kappa monoclonal antibody that binds the co-inhibitory receptor PD-1. Nivolumab binding to PD-1 blocks interaction with the PD-1 ligands PD-L1 and PD-L2. PD-1 blockade can lead to reinvigoration of exhausted T cells and prevent T cell exhaustion of newly activated T cells. Nivolumab has been shown to have excellent clinical efficacy in treating a wide range of cancers as monotherapy and in combination with ipilimumab.

  • CabozantinibDrug

    Also called XL184

    Cabozantinib is a potent small molecule inhibitor of multiple receptor tyrosine kinases. Cabozantinib inhibits VEGFR2, MER, KIT, and MET at single digit nanomolar IC50 concentrations. Other kinases including ROS1, RET, FLT3, RON, AXL, and TIE2 are also inhibited with nanomolar concentrations of cabozantinib. Cabozantinib has been shown to have clinical activity in a variety of solid tumors and has been approved by the FDA for treatment of medullary thyroid cancer, renal cell carcinoma and hepatocellular carcinoma.

Study groups in NCT05200143
Study groupRoleWhat they receive
Cabozantinib + Ipilimumab + NivolumabExperimentalIpilimumab 1 mg/kg + Nivolumab 3 mg/kg IV every 3 weeks + Cabozantinib 40 mg PO daily for 4 cycles followed by Nivolumab 480 mg IV every 4 weeks + Cabozantinib 40 mg PO daily for up to 24 months.
Receives: Drug: Ipilimumab; Drug: Nivolumab; Drug: Cabozantinib

What is being measured

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

  1. Progression Free Survival of the Triplet Combination of Ipilimumab + Nivolumab + Cabozantinib in Patients With Anti-PD-1/PD-L1 Refractory Metastatic Cutaneous Melanoma

    Progression free survival (PFS) will be defined as the time between the date of enrollment and the first date of documented progression (per iRECIST), as determined by the investigator, or death due to any cause, whichever occurs first.

    Measured: 7 Months

Secondary outcomes (2)

  1. Safety/Tolerability (CTCAE v5.0)

    Number of patients who reported incidence of grade ≥3 treatment related adverse events.

    Measured: 13 Months

  2. Overall Survival

    Number of patients who reached the 12 month overall survival timepoint.

    Measured: 12 Months

Timeline

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

  1. First posted20 Jan 2022
  2. Study start8 Jun 2022
  3. Primary completion11 Sep 2023
  4. Study completion23 Jul 2024

Why it stopped: Withdrawn support from BMS.

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
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
4 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05200143
Sponsor's protocol ID
2021000533
Status last verified
Aug 2024
First submitted
6 Jan 2022
Last updated
19 Sep 2024
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ipilimumab, Nivolumab and Cabozantinib in people with Refractory Cutaneous Melanoma, run by Providence Health & Services 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 36 inclusion and 46 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: stopped early, as of the sponsor's last update on 19 Sep 2024. 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 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?

Yes. Results are posted in the registry (first posted 19 Sep 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

Progression Free Survival of the Triplet Combination of Ipilimumab + Nivolumab + Cabozantinib in Patients With Anti-PD-1/PD-L1 Refractory Metastatic Cutaneous Melanoma (time frame: 7 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 NCT05200143.

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 19 Sep 2024.

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