Companies Will Conduct an Exploratory Phase I/II Study in Metastatic Melanoma
NEW YORK, NY, USA | June 2, 2011 | Bristol-Myers Squibb Company (NYSE:BMY – News) announced today it has entered in to a clinical collaboration agreement with Roche (SIX:RO; OTCQX:RHHBY) to evaluate the utility of Bristol-Myers Squibb’s CTLA-4 inhibitor, YERVOY (ipilimumab), in combination with Roche’s investigational oral BRAF inhibitor, vemurafenib, in treating patients with a specific type of metastatic melanoma.
Under the agreement, the two companies will conduct a Phase I/II study to evaluate the safety and efficacy of the combination. If appropriate, the companies may conduct further development of the combination. This agreement represents an important cross-company collaboration exploring the potential role of this regimen in the treatment of metastatic melanoma.
“Metastatic melanoma is one of the most aggressive forms of cancer,” said Brian Daniels, senior vice president, Development and Medical Affairs, Bristol-Myers Squibb. “We are excited to be working with Roche to evaluate the potential that together YERVOY and vemurafenib could improve outcomes for melanoma patients.”
About YERVOY
The U.S. Food and Drug Administration (FDA) approved YERVOY 3 mg/kg for the treatment of patients with unresectable (inoperable) or metastatic melanoma on March 25, 2011 YERVOY is the first and only therapy approved for unresectable or metastatic melanoma to demonstrate a significant improvement in overall survival based on results from a pivotal randomized, double-blind Phase III study (020) that included 676 patients with unresectable or metastatic melanoma who were previously treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. YERVOY is a recombinant, human monoclonal antibody that blocks the cytotoxic T- lymphocyte antigen-4 (CTLA-4), a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses.
The recommended dose of YERVOY is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four doses.
In study 020, median overall survival was 10 months (95% CI: 8.0-13.8) for YERVOY, 6 months (95% CI: 5.5-8.7) for gp100 and 10 months (95% CI: 8.5-11.5) for YERVOY + gp100, with p-values of 0.0026 (not adjusted for multiple comparisons) for YERVOY and 0.0004 for YERVOY + gp100 vs. gp100, respectively. As published in the New England Journal of Medicine in June 2010, the Kaplan-Meier estimated survival rate at 1 year was 46% (95% CI: 37.0, 54.1) in the YERVOY arm vs. 25% (95% CI: 18.1, 32.9) in the gp100 arm. The estimated survival rate at 2 years was 24% (95% CI: 16.0, 31.5) in the YERVOY arm vs. 14%2 (95% CI: 8.0, 20.0) in the gp100 arm.
The full Prescribing Information for YERVOY includes a boxed warning for immune-mediated adverse reactions. YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY (ipilimumab). Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. Patients should be assessed for signs and symptoms of enterocolitis, dermatitis, neuropathy and endocrinopathy and clinical chemistries should be evaluated, including liver function tests and thyroid function tests, at baseline and before each dose. Please see complete Important Safety Information including Boxed WARNING regarding immune-mediated adverse reactions.
Important Safety Information
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.
Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for serve immune-mediated reactions.
Recommended Dose Modifications
Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5mg prednisone or equivalent per day.
Permanently discontinue YERVOY for any of the following:
* Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day.
* Failure to complete full treatment course within 16 weeks from administration of first dose.
* Severe or life-threatening adverse reactions.
Immune-mediated Enterocolitis:
* In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients.
* Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.
* Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus).
o In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.
Immune-mediated Hepatitis:
* In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5X the upper limit of normal (ULN) or total bilirubin elevations >3X the ULN; Grade 3–5) occurred in 8 (2%), with fatal hepatic failure in 0.2% and hospitalization in 0.4%.
* 13 (2.5%) additional YERVOY-treated patients experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5X but ≤5X the ULN or total bilirubin elevation >1.5X but ≤3X the ULN; Grade 2).
* Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY.
o In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution.
Immune-mediated Dermatitis:
* In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) patients.
o 1 (0.2%) patient died as a result of toxic epidermal necrolysis.
o 1 additional patient required hospitalization for severe dermatitis.
* There were 63 (12%) YERVOY-treated patients with moderate (Grade 2) dermatitis.
* Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.
Immune-mediated Neuropathies:
* In the pivotal Phase 3 study in YERVOY-treated patients, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.
* Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported.
* Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia.
Immune-Mediated Endocrinopathies:
* In the pivotal Phase 3 study in YERVOY- treated patients, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%).
o All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism.
o 6 of the 9 patients were hospitalized for severe endocrinopathies.
* Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome.
* Median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY.
* Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism.
o Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease.
o Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.
o Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms.
o In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.
Other Immune-mediated Adverse Reactions, Including Ocular Manifestations:
* In the pivotal Phase 3 study in YERVOY-treated patients, clinically significant immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia.
* Across the clinical development program for YERVOY, immune-mediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis.
Pregnancy & Nursing:
* YERVOY is classified as pregnancy category C. There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.
* Human IgG1 is known to cross the placental barrier and YERVOY is an IgG1; therefore, YERVOY has the potential to be transmitted from the mother to the developing fetus.
* It is not known whether YERVOY is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY.
Common Adverse Reactions:
* The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).
Please see full Prescribing Information, including BOXED Warning regarding immune-mediated adverse reactions at www.YERVOY.com or www.bms.com.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit www.bms.com, or follow us on Twitter at http://twitter.com/bmsnews.
SOURCE: Bristol-Myers Squibb
