On June 17, 2017 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company developing innovative cellular immunotherapies for the treatment of cancer, today reported data from the TRANSCEND trial of JCAR017 in relapsed and refractory (r/r) aggressive B cell non-Hodgkin lymphoma (NHL) at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland (Press release, Juno, JUN 17, 2017, View Source [SID1234519575]).

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JCAR017 is Juno’s investigative chimeric antigen receptor (CAR) T cell product candidate that targets CD19, a protein expressed on the surface of almost all B cell malignancies, and uses a defined composition of CD4 to CD8 T cells and a 4-1BB costimulatory domain, which differentiates it from other current CD19-directed CAR T product candidates. JCAR017 has been granted Breakthrough Therapy designation by the FDA for treatment of r/r aggressive large B cell NHL and PRIME designation by the European Medicines Agency for treatment of r/r diffuse large B cell lymphoma (DLBCL), a type of NHL.

"We are pleased to again present TRANSCEND data, which show compelling results in the treatment of aggressive relapsed or refractory NHL," said Sunil Agarwal, M.D., Juno’s President of Research and Development. "High rates of durable responses and the early survival data are especially exciting, as is the emerging safety profile. The majority of TRANSCEND patients experienced no cytokine release syndrome or neurotoxicity at all. While still early, these data suggest that JCAR017 could be administered on an outpatient basis."

Data were presented by Jeremy Abramson, M.D., of Massachusetts General Hospital Cancer Center, from the multicenter TRANSCEND trial (ABSTRACT #128), a Phase 1 study that has treated a total of 67 patients with r/r aggressive B cell NHL, including those with DLBCL or follicular lymphoma grade 3B, as of a data cutoff date of May 4, 2017.

TRANSCEND NHL 001 is a dose-finding study of JCAR017, which is administered following fludarabine/cyclophosphamide lymphodepletion. Patients received one of two dose levels (50 or 100 million cells). They were then evaluated for pharmacokinetics, disease response, and safety outcomes, including common CAR T side effects such as cytokine release syndrome (CRS) and neurotoxicity (NT).

Notably, the TRANSCEND NHL 001 protocol includes patients with forms of B cell NHL that would exclude them from trials of other CAR T product candidates, including those with ECOG 2 performance status, central nervous system (CNS) involvement of their lymphoma, and those relapsed after allogeneic bone marrow transplant.

Data for the DLBCL cohort were presented in two groups: core and full. The core analysis group (N=44) includes patients that represent the population that Juno plans to move forward into a pivotal trial in the second half of 2017. The core group includes patients with DLBCL (de novo and transformed from follicular lymphoma) that are ECOG Performance Status 0-1. The full analysis group includes all r/r patients in the DLBCL cohort (N=55), including 11 patients with poor performance status or niche subtypes of aggressive NHL. Both the core and full groups received conforming product, with at least one month follow-up, and with a data cutoff date of May 4, 2017, for this presentation.

"CAR T cell therapy represents an important step forward in providing options for these highly chemotherapy refractory patients and addresses a significant unmet medical need," said Dr. Abramson. "I am particularly excited about the emerging efficacy and safety profile with JCAR017, which could ultimately prove to be optimal therapy for patients with relapsed and refractory DLBCL."

Key data and findings:
Core Group (N=44)
Combining data across dose levels:
Overall response rate (ORR) is 86% (38/44) and the complete response (CR) is 59% (26/44).
Three-month ORR is 66% (21/32) and CR is 50% (16/32). Of patients in response at three months, 90% (9/10) continue in response at six months.

Early data suggest a dose response relationship at three months:
Dose level 1 (50 million cells) ORR is 58% (11/19) and CR is 42% (8/19).
Dose level 2 (100 million cells) ORR is 78% (7/9) and CR is 56% (5/9).
97% (37/38) of responding patients are alive and in follow-up as of May 4, 2017.
2% (1/44) experienced severe CRS and 18% (8/44) experienced severe NT.
66% (29/44) did not experience any CRS or NT. No deaths were reported from CRS or NT.
There was one Grade 5 adverse event of diffuse alveolar damage, which the investigator assessed as possibly related to fludarabine, cyclophosphamide, and JCAR017 treatment, occurring on day 23 in an 82-year-old subject who refused mechanical ventilation for progressive respiratory failure while neutropenic on growth factors and broad spectrum antibiotics and antifungals. This patient had no CRS and Grade 3 neurotoxicity resolution before the Grade 5 event.

Full Dataset (N=55)
Combining data across dose levels:
Best ORR is 76% (41/54) and CR is 52% (28/54).
Three-month ORR is 51% (21/41) and CR is 39% (16/41).
2% (1/55) experienced severe CRS and 16% (9/55) experienced severe NT. 60% (33/55) did not experience any CRS or NT. No deaths reported from CRS or NT.
Early data do not suggest a dose toxicity relationship at the doses tested:
Severe CRS rate is 3% (1/30) at dose level 1 and 0% (0/19) at dose level 2.
Severe NT rate is 20% (6/30) at dose level 1 and 11% (2/19) at dose level 2.
11% (6/55) received tocilizumab and 24% (13/55) received dexamethasone.
The most frequently reported treatment-emergent adverse events were neutropenia (35%), CRS (35%), and fatigue (31%).

Manufacturing
Product was available for 98% (86/88) of patients apheresed. TRANSCEND patients receive product made at JuMP, Juno’s manufacturing facility in Bothell, Washington. Juno expects commercial production will be accomplished in less than 21 days, and Juno is investing in manufacturing infrastructure to enable a smooth prescribing experience with a reliable delivery time at market entry.

About Juno’s Chimeric Antigen Receptor (CAR) and T Cell Receptor (TCR) Technologies
Juno’s CAR and TCR technologies genetically engineer T cells to recognize and kill cancer cells. Juno’s CAR T cell technology inserts a gene for a particular CAR into the T cell, enabling it to recognize cancer cells based on the expression of a specific protein located on the cell surface. Juno’s TCR technology provides the T cells with a specific T cell receptor to recognize protein fragments derived from either the surface or inside the cell. When either type of engineered T cell engages the target protein on the cancer cell, it initiates a cell-killing response against the cancer cell. JCAR014 and JCAR017 are investigational product candidates and their safety and efficacy have not been established.

On June 17, 2017 Celgene Corporation (NASDAQ: CELG) reported results from an interim analysis of MAGNIFY, a phase IIIb, randomized, open-label, multicenter study of REVLIMID (lenalidomide) plus rituximab (R2) combination therapy in patients with relapsed or refractory marginal zone lymphoma (MZL) (Press release, Celgene, JUN 17, 2017, View Source [SID1234519572]). Results were presented at the International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland and expanded upon data presented earlier in the month at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting in Chicago, Ill.

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The MAGNIFY study continues to evaluate the clinical activity of 12 cycles of R2 combination therapy followed by randomization to either 18 cycles of R2 maintenance or 18 cycles of rituximab monotherapy, in patients with relapsed or refractory follicular lymphoma (FL), marginal zone lymphoma (MZL) or mantle cell lymphoma (MCL). Approximately 500 patients are planned to be enrolled in the study. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), overall response rate (ORR), complete response (CR), improvement of response (IOR), duration of response (DOR) and duration of complete response (DOCR), time to next lymphoma treatment (TTNLT), time to histological transformation (TTHT), safety and exploratory quality of life measures. Enrollment in the MAGNIFY study is ongoing.

"Interim data from the MAGNIFY study continue to show the clinical potential for the R2 combination across a broad range of lymphomas," said Michael Pehl, President, Hematology/Oncology at Celgene. "As we await data from our late-stage programs, including the phase III AUGMENT and RELEVANCE studies, we hope that the growing volume of evidence for R2 may lead to new options for patients that offer an alternative to traditional cytotoxic chemotherapies."

At ASCO (Free ASCO Whitepaper), interim data were presented from an analysis of a subset of patients from the MAGNIFY study with relapsed or refractory FL (n=160) with early relapse (ER, n=52) and double-refractory (DR, n=50) disease. At the January 9, 2017 data cut-off, the 1-year PFS for all FL patients was 70%, with 65% for DR patients and 49% for ER patients. Additionally, evaluable FL patients (n=128) had an ORR of 66% with a CR/CRu rate of 38%. For DR patients (n=42), ORR was 45% with a CR/CRu rate of 21% and for ER patients (n=43), ORR was 47% with a CR/CRu rate of 21%. Median DOR was not met at a median follow-up of 10.2 months.

Most common grade 3 or 4 adverse events observed in the study for all FL patients, DR patients and ER patients, respectively, were neutropenia (29%, 42%, 37%), fatigue (6%, 4%, 8%), leukopenia (5%, 8%, 10%), thrombocytopenia (4%, 8%, 4%) and lymphopenia (3%, 6%, 4%).

Data being presented at ICML in a separate analysis focused on patients with MZL (n=38), including nodal MZL (n=18), splenic MZL (n=10) and mucosa-associated lymphoid tissue (MALT) lymphoma (n=10). At a median follow-up of 13.8 months from initiation of therapy with the R2 combination, evaluable patients with MZL (n=32) achieved an ORR of 66% with a CR/CRu rate of 44%. Evaluable nodal MZL patients (n=14) had an ORR of 57% with a CR/CRu rate of 57%. Evaluable splenic MZL patients (n=8) had an ORR of 63% with a CR of 25%; and evaluable MALT patients (n=10) had an ORR of 80% with a CR/CRu rate of 40%. Median duration of response was not reached for any group.

The most common grade 3 or 4 adverse events observed in patients with MZL were neutropenia (32%), thrombocytopenia (16%) and leukopenia (11%).

"The chemotherapy-free combination of lenalidomide and rituximab, with complementary mechanisms of action that are thought to enhance antibody dependent cellular cytotoxicity, continues to show encouraging activity and a tolerable safety profile in indolent lymphomas, and particularly in difficult-to-treat patient subsets," said David J. Andorsky, M.D., co-principal investigator of the study and medical oncologist at the Rocky Mountain Cancer Centers in Boulder, CO. "These results in patients who had failed multiple therapies or relapsed early, as well as the activity in marginal zone patients merit further study in this area of indolent lymphoma."

About MAGNIFY

MAGNIFY (NCT01996865) is a phase IIIb, multicenter, open-label study of patients with grades 1-3b or transformed FL, MZL, or MCL who received ≥1 prior therapy and had stage I-IV, measurable disease. Approximately 500 patients are planned for enrollment in 12 cycles of R2 induction, with a projected 314 patients with ≥SD after induction randomized (1:1) to two maintenance arms. Induction included oral lenalidomide 20 mg/day, days 1-21 per 28-day cycle (d1-21/28) plus intravenous rituximab 375 mg/m2, days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3, 5, 7, 9, and 11 (28-day cycles). Patients are then randomized to maintenance lenalidomide 10 mg/day, d1-21/28, cycles 13-30, plus rituximab 375 mg/m2, day 1 of cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 (R2, Arm A), or rituximab alone (same schedule, Arm B). Patients receiving R2 maintenance after 18 cycles may continue maintenance lenalidomide monotherapy 10 mg/day, d1-21/28 (per patient and/or investigator discretion), until disease progression as tolerated. Patients will be followed for ≥5 years after the last patient initiates induction therapy.

About Follicular and Marginal Zone Lymphomas

FL is the most common indolent (slow-growing) form of NHL, accounting for approximately 22% of all B-cell Non-Hodgkin lymphoma (NHL) patients. Most patients present with advanced disease usually when lymphoma-related symptoms appear (e.g., nodal disease, B symptoms, cytopenia) and receive systemic chemoimmunotherapy. While FL patients are generally responsive to initial treatment, the disease course is characterized by recurrent relapses over time with shorter remission periods. MZL are a heterogeneous group of indolent lymphomas that account for 8% of all NHL. While often treated like FL, MZL has important differences in clinical presentation and pathogenesis. Patients with MZL have historically been grouped within studies of mixed indolent NHL histologies, and large studies are lacking to validate appropriate treatment for MZL patients.

REVLIMID was granted Orphan Drug Designation for the treatment of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue in April 2015.

REVLIMID is not approved for combination use with rituximab for any purpose or for the treatment of follicular lymphoma or marginal zone lymphoma.

About REVLIMID

REVLIMID (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM)

REVLIMID is indicated as maintenance therapy in patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT)

REVLIMID is indicated for the treatment of patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities

REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib

REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity

Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS program).

Information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)

REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.

Venous and Arterial Thromboembolism

REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus

Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: See Boxed WARNINGS

Females of Reproductive Potential: See Boxed WARNINGS
Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm
Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID
REVLIMID REMS Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the REVLIMID REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements

Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex or REVLIMID maintenance therapy should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. MDS: Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or dose reduction. Please see the Boxed WARNINGS for further information. MCL: Patients taking REVLIMID for MCL should have their CBCs monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction

Venous and Arterial Thromboembolism: See Boxed WARNINGS: Venous thromboembolic events (DVT and PE) and arterial thromboses (MI and CVA) are increased in patients treated with REVLIMID. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended and the regimen should be based on patient’s underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision

Increased Mortality in Patients with CLL: In a clinical trial in the first-line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving REVLIMID, an increase of hematologic plus solid tumor SPM, notably AML and MDS, have been observed. Monitor patients for the development of SPM. Take into account both the potential benefit of REVLIMID and risk of SPM when considering treatment

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID/dex. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered

Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose; risk-benefit of treatment should be evaluated in patients with lactose intolerance

Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken

Tumor Flare Reaction (TFR): TFR has occurred during investigational use of lenalidomide for CLL and lymphoma. Monitoring and evaluation for TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤ Grade 1. REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment ( > 4 cycles) with REVLIMID has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection

Thyroid Disorders: Both hypothyroidism and hyperthyroidism have been reported. Measure thyroid function before start of REVLIMID treatment and during therapy

ADVERSE REACTIONS

Multiple Myeloma

In newly diagnosed: The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more Grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18
The most common adverse reactions reported in ≥20% (Arm Rd Continuous): diarrhea (46%), anemia (44%), neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash (26%), decreased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%), abdominal pain (21%), muscle spasms (20%), and thrombocytopenia (20%)
Maintenance Therapy Post Auto-HSCT: The most frequently reported Grade 3 or 4 reactions in ≥20% (REVLIMID arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions of lung infection and neutropenia (more than 4.5%) occurred in the REVLIMID arm
The most frequently reported adverse reactions in ≥20% (REVLIMID arm) across both maintenance studies (Study 1, Study 2) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%)
After at least one prior therapy: The most common adverse reactions reported in ≥20% (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), and weight decreased (20% vs 15%)
Myelodysplastic Syndromes

Grade 3 and 4 adverse events reported in ≥ 5% of patients with del 5q MDS were neutropenia (53%), thrombocytopenia (50%), pneumonia (7%), rash (7%), anemia (6%), leukopenia (5%), fatigue (5%), dyspnea (5%), and back pain (5%)
Adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): thrombocytopenia (61.5%), neutropenia (58.8%), diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)
Mantle Cell Lymphoma

Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%)
Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%)
DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels is recommended due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant warfarin

USE IN SPECIFIC POPULATIONS:

PREGNANCY: See Boxed WARNINGS: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. There is a REVLIMID pregnancy exposure registry that monitors pregnancy outcomes in females exposed to REVLIMID during pregnancy as well as female partners of male patients who are exposed to REVLIMID. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to REVLIMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436
LACTATION: There is no information regarding the presence of lenalidomide in human milk, the effects of REVLIMID on the breastfed infant, or the effects of REVLIMID on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants from REVLIMID, advise female patients not to breastfeed during treatment with REVLIMID
PEDIATRIC USE: Safety and effectiveness have not been established in pediatric patients
RENAL IMPAIRMENT: Adjust the starting dose of REVLIMID based on the creatinine clearance value and for patients on dialysis
Please see full Prescribing Information, including Boxed WARNINGS.

On June 16, 2017 Genmab A/S (Nasdaq Copenhagen: GEN) reported preliminary data from the ongoing Phase I/II study of tisotumab vedotin in solid tumors (GEN701) (Press release, Genmab, JUN 16, 2017, View Source [SID1234519590]). In Part 2 of the study, 11 of 34 evaluable patients in the cervical cancer cohort achieved a response; with a median time of treatment of 4.9 months, 7 responders are still ongoing or in follow up for progression. The safety profile of tisotumab vedotin was consistent with known MMAE based antibody-drug conjugates (ADC), including peripheral neuropathy and neutropenia. Additionally, conjunctivitis was identified as a tisotumab vedotin specific toxicity, which led to introducing of prophylactic management. In the cervical cancer cohort, 15 patients experienced one or more Grade 3 adverse events: gastro-intestinal related (5 patients), anemia (2 patients), infections (1 patient), neuropathy (2 patients), bleeding (2 patients), other (10 patients). Genmab is considering plans for further clinical development of tisotumab vedotin in cervical cancer. The GEN701 study is ongoing and further data in both cervical cancer and other solid tumor indications will be published at a later date.

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"The preliminary data we see in patients with cervical cancer treated with tisotumab vedotin are encouraging. We believe further development of this novel antibody-drug conjugate may be warranted in cervical cancer and are actively looking into possible next steps," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.
Genmab intends to submit data from this study for presentation at an upcoming medical conference.

About the GEN701 study
The GEN701 study is a 173 patient, two-part Phase I/II study of tisotumab vedotin in seven types of solid tumors: ovarian, cervical, endometrium, bladder, prostate, esophageal, and lung. Part 1 was a classical 3+3 dose escalation design testing various doses of tisotumab vedotin once every three weeks to establish the recommended Phase II (RP2D) and maximum tolerated dose as well as the safety profile of tisotumab vedotin. The still ongoing Part 2 of the study investigates all seven indications in parallel expansion cohorts. Patients receive 2.0 mg/kg (=RP2D) of tisotumab vedotin once every three weeks. The primary objective of this part of the study is to further investigate the safety profile of tisotumab vedotin and preliminary efficacy.

About tisotumab vedotin
Tisotumab vedotin is an antibody-drug conjugate (ADC) composed of a human antibody that binds to tissue factor (TF) conjugated to Seattle Genetics’ clinically validated cytotoxic drug MMAE. TF is a protein involved in tumor signaling and angiogenesis. Based on its high expression on many solid tumors and its rapid internalization, TF was selected as a target for an ADC approach. Tisotumab vedotin is in Phase I/II clinical development for solid tumors in two studies (GEN701 and GEN702). Genmab has a license and collaboration agreement for tisotumab vedotin with Seattle Genetics under which Seattle Genetics has the right to exercise a co-development option at the end of Phase I clinical development.

On June 16, 2017 Genmab A/S (Nasdaq Copenhagen: GEN) reported the U.S. Food and Drug Administration (FDA) has approved the use of DARZALEX (daratumumab) in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor (Press release, Genmab, JUN 16, 2017, View Source [SID1234519581]). DARZALEX is being developed under an August 2012 agreement in which Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize the product. Genmab will receive milestone payments totaling USD 25 million from Janssen in connection with the approval and first commercial sale of DARZALEX under the newly expanded label. The sale is expected to occur quickly after the approval. The approval and related milestones do not impact the financial guidance issued by Genmab on May 10, 2017.

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"We are very pleased to receive the FDA’s decision to approve DARZALEX in combination with pomalidomide and dexamethasone. This offers another alternative to patients with multiple myeloma who haven’t seen lasting effects from other types of treatment," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.
The approval was based on data from the Phase I (MMY1001, EQUULEUS) study of daratumumab in combination with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma.

About the EQUULEUS study
The Phase I EQUULEUS open-label study, Pom-D arm, included 103 patients with multiple myeloma who had received prior treatment with a proteasome inhibitor (PI) and an immunomodulatory agent. Patients in the study received 16 mg/kg daratumumab in combination with pomalidomide and dexamethasone. The overall response rate in the study was 59% (95% CI: 49.1%, 68.8%), with very good partial response (VGPR) achieved in 28% of patients. Complete response (CR) was achieved in 6% of patients and stringent CR (sCR) was achieved in 8% of patients. The median time to response was 1 month (range: 0.9 to 2.8 months). The median duration of response was 13.6 months (range: 0.9+ to 14.6+ months). The most frequent adverse reactions (>20%) in the study were: infusion reactions (50%), diarrhea (38%), nausea (30%), vomiting (21%), fatigue (50%), pyrexia (25%), upper respiratory tract infection (50%), muscle spasms (26%), cough (43%) and dyspnea (33%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions (Grade 3/4) reported in ≥5% patients included pneumonia (7%). The most common treatment-emergent hematology laboratory abnormalities were lymphopenia (94%), neutropenia (95%), thrombocytopenia (75%) and anemia (57%). The most common Grade 3/4 treatment-emergent hematology laboratory abnormalities were neutropenia (82%), lymphopenia (71%), anemia (30%) and thrombocytopenia (20%).

The median age of patients in the study was 64 years with 8% of patients older than 75. Patients in the study had received a median of four prior lines of therapy, and 74% of patients had received prior autologous stem cell transplant (ASCT). Eighty-nine percent of patients were refractory to lenalidomide and 71% were refractory to bortezomib; 64% of patients were refractory to bortezomib and lenalidomide.

About multiple myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.1 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.2 Approximately 30,330 new patients were expected to be diagnosed with multiple myeloma and approximately 12,650 people were expected to die from the disease in the U.S. in 2016.3 Globally, it was estimated that 124,225 people would be diagnosed and 87,084 would die from the disease in 2015.4 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.5 Patients who relapse after treatment with standard therapies, including proteasome inhibitors or immunomodulatory agents, have poor prognoses and few treatment options.6

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy; in combination with pomalidomide and dexamethasone for the treatment of with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI); and as a monotherapy for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.7 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy and as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. DARZALEX is the first human CD38 monoclonal antibody approved in Europe. For more information, visit www.DARZALEX.com.
Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. Daratumumab triggers a person’s own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death, via apoptosis (programmed cell death). 7,8,9,10,11

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline multiple myeloma settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma, NKT-cell lymphoma, amyloidosis, myelodysplastic syndromes and solid tumors. Daratumumab has received two Breakthrough Therapy Designations from the U.S. FDA, for multiple myeloma, as both a monotherapy and in combination with other therapies.

IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS – None

WARNINGS AND PRECAUTIONS
Infusion Reactions — DARZALEX can cause severe infusion reactions. Approximately half of all patients experienced a reaction, most during the first infusion. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing an infusion. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy for life-threatening (Grade 4) reactions. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Interference with Serological Testing – Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.

Neutropenia – DARZALEX may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX dose delay may be required to allow recovery of neutrophils. No dose reduction of DARZALEX is recommended. Consider supportive care with growth factors.

Thrombocytopenia – DARZALEX may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. DARZALEX dose delay may be required to allow recovery of platelets. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions.

Interference with Determination of Complete Response – Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both, the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions — In patients who received DARZALEX in combination with lenalidomide and dexamethasone, the most frequently reported adverse reactions (incidence ≥20%) were: neutropenia (92%), thrombocytopenia (73%), upper respiratory tract infection (65%), infusion reactions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The overall incidence of serious adverse events was 49%. Serious adverse reactions were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%) and pyrexia (3%).

In patients who received DARZALEX in combination with bortezomib and dexamethasone, the most frequently reported adverse reactions (incidence >20%) were: thrombocytopenia (90%), neutropenia (58%), peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse events was 42%. Serious adverse reactions were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation (2%).
In patients who received DARZALEX in combination with pomalidomide and dexamethasone, the most frequently reported adverse reactions (incidence >20%) were: infusion reactions (50%), diarrhea (38%), nausea (30%), vomiting (21%), fatigue (50%), pyrexia (25%), upper respiratory tract infection (50%), muscle spasms (26%), cough (43%) and dyspnea (33%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions (Grade 3/4) reported in ≥5% patients included pneumonia (7%). The most common treatment-emergent hematology laboratory abnormalities were lymphopenia (94%), neutropenia (95%), thrombocytopenia (75%) and anemia (57%). The most common Grade 3/4 treatment-emergent hematology laboratory abnormalities were neutropenia (82%), lymphopenia (71%), anemia (30%) and thrombocytopenia (20%).

In patients who received DARZALEX as monotherapy, the most frequently reported adverse reactions (incidence ≥20%) were: neutropenia (60%), thrombocytopenia (48%), infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).

DRUG INTERACTIONS
Effect of Other Drugs on daratumumab: The coadministration of lenalidomide, pomalidomide or bortezomib with DARZALEX did not affect the pharmacokinetics of daratumumab.

Effect of Daratumumab on Other Drugs: The coadministration of DARZALEX with bortezomib did not affect the pharmacokinetics of bortezomib.