On December 2, 2018 Magenta Therapeutics (NASDAQ:MGTA), a clinical-stage biotechnology company developing novel medicines to bring the curative power of bone marrow transplant to more patients, reported that the Company presented preclinical research on its targeted conditioning programs at the 60th annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (Press release, Magenta Therapeutics, DEC 2, 2018, View Source [SID1234531798]).

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Patients undergoing bone marrow transplant or stem cell gene therapy are first prepared, or conditioned, with non-specific, genotoxic chemotherapy alone or in combination with total body irradiation. This conditioning process is associated with significant toxicity, including development of cancers, infertility, organ toxicities, or even death. As a result, many patients do not consider undergoing a bone marrow transplant or gene therapy. Magenta is developing a portfolio of targeted antibody drug conjugates (ADCs), including non-genotoxic agents, that selectively remove the specific cells to enable a successful transplant or gene therapy procedure.

"This year’s five ASH (Free ASH Whitepaper) data presentations from our portfolio of targeted conditioning programs give further insight into our progress in addressing one of the major challenges of the transplant and gene therapy process: the genotoxic conditioning that leaves patients infertile and puts them at risk for malignancies and organ toxicity," said Michael Cooke, Ph.D., chief scientific officer, Magenta Therapeutics. "Our most advanced targeted conditioning program, C200, is focused on ADCs directed at CD117, a target expressed on stem cells and many types of leukemia cells. Preclinical data at ASH (Free ASH Whitepaper) this year show potent and selective depletion of human and non-human primate stem cells with our non-genotoxic CD117 ADC conjugated to amanitin. In addition, both this ADC and our CD45-targeted ADC from our C100 program demonstrated the additional benefit of anti-leukemia activity and survival advantage in patient-derived leukemia models. Based on these promising data, we are finalizing the CD117 and CD45 ADCs, and we expect to select a lead for development for the CD117 program to launch IND-enabling studies in 2019."

CD117-Amanitin Antibody Drug Conjugates Effectively Deplete Human and Non-Human Primate HSCs: Proof of Concept as a Targeted Strategy for Conditioning Patients for Bone Marrow Transplant, Abstract #3314

Key results, presented by Brad Pearse, Ph.D., Magenta Therapeutics:

An anti-CD117 ADC conjugated with amanitin potently depleted human and non-human primate hematopoietic stem cells and progenitors in vivo.
An anti-CD117 amanitin ADC with engineered fast half-life showed potent stem cell depletion and rapid clearance, providing appropriate pharmacokinetics for patient preparation for bone marrow transplant.
The ADCs were well tolerated at the efficacious doses.
Potent and selective depletion of stem cells with rapid clearance of the ADC could provide a significant improvement over current approaches to patient preparation with an acceptable safety profile prior to BMT for malignancies, autoimmune diseases and gene therapies, broadening patient access to these potentially curative therapies.
Magenta will next finalize the linker-toxin construct and select a lead for development in 2018, then begin IND-enabling studies in 2019.
Single Doses of Antibody Drug Conjugates (ADCs) Targeted to CD117 or CD45 Have Potent In Vivo Anti-Leukemia Activity and Survival Benefit in Patient-Derived AML Models, Abstract #3316

Key results, presented by Jennifer Proctor, Magenta Therapeutics:

CD117 is expressed on human hematopoietic stem and progenitor cells and on leukemia cells in 80% of patients with acute myeloid leukemia (AML) and in 65% of patients with myelodysplastic syndromes (MDS); CD45 is expressed on all lympho-hematopoietic cells and in nearly all blood cancers, other than multiple myeloma.
Both the anti-CD117 amanitin ADC (C200 program) and the anti-CD45 amanitin ADC (C100 program) showed potent killing of human hematopoietic stem cells and human leukemia cell lines expressing these targets in vitro.
A single dose of either ADC showed potent in vivo anti-leukemia activity in mice bearing established human leukemia cell lines.
Both ADCs also significantly improved the survival of mice engrafted with human leukemia cells from AML patients, including leukemias that were resistant to multiple lines of therapy including previous allogeneic bone marrow transplant.
Magenta Therapeutics’ C200 and C100 programs are designed with the dual intent of selectively eliminating the necessary cells to enable a successful transplant and reducing disease burden in patients with active disease or in patients who are at high risk of disease relapse.
Magenta will next finalize the linker-toxin constructs, select anti-CD117 and anti-CD45 leads for development and continue to progress ADC-based conditioning approaches targeting CD45 and CD117 toward clinical development.
Antibody Drug Conjugates Targeted to CD45 or CD117 Enable Allogeneic Hematopoietic Stem Cell Transplantation in Animal Models, Abstract #3324

Key results, presented by Sharon Hyzy, M.S., Magenta Therapeutics:

ADCs targeted to mouse CD45 or mouse CD117 have been shown to effectively condition immunocompetent mice for autologous bone marrow transplant.
To investigate the utility of these murine-specific tool ADCs conjugated to saporin to enable allogenic transplant, Magenta assessed these ADCs as single agents or in combination with immunosuppressive agents to facilitate transplant in a murine allogeneic transplant model.
Both anti-CD45 and anti-CD117 saporin ADCs, when combined with additional immunosuppressants, enabled successful minor mismatch whole bone marrow transplants in mouse models.
Conditioning with the anti-CD45 saporin ADC plus post-transplant cyclophosphamide to prevent graft vs. host disease enabled successful engraftment across minor histocompatibility antigens.
The ADCs were more effective than an unconjugated anti-CD45 antibody, pre-transplant cyclophosphamide, or sublethal irradiation in combination with post-transplant cyclophosphamide.
Magenta will next investigate other linker-toxins as well as ADC-based conditioning in various allogeneic mouse models.
Non-genotoxic conditioning facilitates robust HSPC engraftment and multi-lineage development in a dose dependent manner in Fanconi anemia, Abstract #2041

Key results, presented by Meera Srikanthan, Ph.D., Fred Hutchinson Cancer Research Center:

Conditioning with genotoxic chemotherapy in patients with Fanconi anemia is currently utilized to open the bone marrow niche prior to infusion of hematopoietic stem cells in a bone marrow transplant but is often associated with genotoxic effects.
ADCs targeting hematopoietic stem cells are an emerging non-genotoxic method of conditioning, particularly in diseases associated with DNA damage and cancer predisposition, such as Fanconi anemia.
Researchers at the Fred Hutchinson Cancer Research Center sought to study the application of non-genotoxic ADC-based conditioning targeting hematopoietic stem cells to eliminate leukemogenic host HSCs and to facilitate the engraftment of donor cells.
Results showed that the immunotoxin-based conditioning drugs from Magenta are of similar if not superior efficacy compared to cyclophosphamide, facilitating multi-lineage engraftment of autologous stem cells, as would be used in gene therapy.
Researchers at the Fred Hutchinson Cancer Research Center will next determine whether immunotoxin conditioning facilitates engraftment of gene-modified stem cells using FancA (-/-) mice and optimize dosing of immunotoxin platform to completely eliminate host hematopoiesis in order to decrease the risk of leukemogenesis.
Targeting CD45 with an Amanitin Antibody-Drug Conjugate Effectively Depletes Human HSCs and Immune Cells for Transplant Conditioning, Abstract #4526

Key results will be presented by Rahul Palchaudhuri, Ph.D., Magenta Therapeutics, on Monday, December 3, 2018.

A human/primate cross-reactive anti-CD45 amanitin ADC potently depletes human hematopoietic stem cells and immune cells in culture.
The anti-CD45 ADC achieved efficient depletion of immune cells in the periphery and hematopoietic stem cells in the bone marrow of humanized mice.
Simultaneous depletion of immune and hematopoietic stem cells using an anti-CD45 ADC may enable safer conditioning for allogeneic transplant and enable immune-reset in autoimmune disease transplantation.
Magenta plans to optimize the anti-CD45 ADC and select a development candidate in 2019, with IND-enabling studies to begin in 2020.

On December 2, 2018 Celgene Corporation (NASDAQ: CELG) reported results of the phase 3 AUGMENT study, which showed that REVLIMID (lenalidomide) in combination with rituximab (R2) demonstrated superior progression-free survival (PFS) in patients with relapsed/refractory indolent lymphoma compared to patients who received rituximab plus placebo (R-placebo) (Press release, Celgene, DEC 2, 2018, View Source [SID1234531797]). The data were presented by John Leonard, M.D. in an oral presentation at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, C.A. (Abstract #445).

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The phase 3 randomized, double-blind, international clinical study evaluated the efficacy and safety of the investigational combination of R2 versus rituximab plus placebo in patients (n=358) with relapsed/refractory follicular (n=295) and marginal zone (n=63) lymphoma.

In the study, the R2 arm demonstrated a highly statistically significant improvement in the primary endpoint of progression-free survival (PFS), evaluated by an independent review committee, versus (vs.) the R-placebo arm. The median PFS was 39.4 months for patients treated with R2 and 14.1 months for those treated with R-placebo (P <0.0001; HR: 0.46; 95% CI, 0.34-0.62).

"The AUGMENT data, with R2 more than doubling progression-free survival over rituximab monotherapy, represents an important potential new treatment option for patients with relapsed/refractory follicular or marginal zone lymphoma," said John Leonard, M.D., AUGMENT lead investigator, The Richard T. Silver Distinguished Professor of Hematology and Medical Oncology and director of the Joint Clinical Trials Office at Weill Cornell Medicine, who has also served as a consultant for Celgene.

Overall survival (OS), a secondary endpoint, showed a positive trend for improvement in the R2 arm vs. the control arm (16 vs. 26 death events) (HR: 0.61; 95% CI, 0.33-1.13). Two-year OS rate was 93% for patients receiving R2 and 87% for those receiving R-placebo.

Overall response rate (ORR), another secondary endpoint, was 78% (n=138) in the R2 arm vs. 53% (n=96) in the R-placebo arm, according to the independent review committee. Duration of response (DoR) was significantly improved for R2 vs. R-placebo with median DoR of 37 vs. 22 months, respectively (P =0.0015; HR: 0.53; 95% CI, 0.36-0.79).

The most frequent adverse event (AE) in the R2 arm was neutropenia (58%), vs. 22% in the R-placebo arm. Additional commonly observed AEs in more than 20% of patients included diarrhea (31% in the R2 arm vs. 23% in R-placebo), constipation (26% vs. 14%, respectively), cough (23% vs. 17%), and fatigue (22% vs. 18%), respectively. Adverse events that were reported at a higher rate (>10%) in the R2 arm were neutropenia, constipation, leukopenia, anemia, thrombocytopenia and tumor flare. No unexpected safety findings were observed in the AUGMENT trial.

"These data represent a potential new treatment strategy for patients with relapsed/refractory indolent non-Hodgkin’s lymphomas," said Alise Reicin, M.D., President, Global Clinical Development for Celgene. "We are advancing regulatory submissions in the first quarter of 2019 to bring this important combination to patients as soon as possible."

REVLIMID alone or in combination with other agents is not approved for use in follicular lymphoma or marginal zone lymphoma in any geography.

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

Severe Hypersensitivity Reactions: REVLIMID is contraindicated in patients who have demonstrated severe 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 as 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 Black Box 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

Increased Mortality with Pembrolizumab: In clinical trials in patients with multiple myeloma, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials

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

Severe Cutaneous Reactions Including Hypersensitivity Reactions: Angioedema and severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash, or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. 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, TEN, or DRESS is suspected and should not be resumed following discontinuation for these reactions

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

Early Mortality in Patients with MCL: In another MCL study, there was an increase in early deaths (within 20 weeks), 12.9% in the REVLIMID arm versus 7.1% in the control arm. Risk factors for early deaths include high tumor burden, MIPI score at diagnosis, and high WBC at baseline (≥10 x 109/L)

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 in patients on dialysis

On December 2, 2018 bluebird bio, Inc. (Nasdaq:BLUE) and Celgene Corporation (NASDAQ:CELG) reported initial data from the ongoing Phase 1 clinical study of bb21217 (CRB-402), an investigational next-generation anti-BCMA CAR T cell therapy being studied in patients with relapsed/refractory multiple myeloma (Press release, bluebird bio, DEC 2, 2018, View Source [SID1234531796]). The data were presented by Nina Shah, M.D., University of California, San Francisco, as an oral presentation at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper).

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bb21217 is an investigational anti-BCMA CAR T cell therapy that uses the bb2121 chimeric antigen receptor (CAR) molecule with a manufacturing process designed to improve CAR T cell functional persistence. bb21217 has exhibited improved functional persistence and increased anti-tumor activity in preclinical animal studies.

"Anti-BCMA CAR T therapy with bb2121 has shown clinical responses in a substantial proportion of patients with relapsed/refractory multiple myeloma. With the bb21217 program we are pursuing an approach intended to improve the in vivo persistence of functional CAR T cells with the hope that this provides a more durable benefit for patients," said David Davidson, M.D., chief medical officer, bluebird bio. "The safety results and promising response rate in the initial dose cohort, as well as the observation of detectable CAR T cells in the first three patients with follow up to the month 6 study visit and beyond, support advancing to a higher dose to further characterize the potential of bb21217 as a treatment option for patients with relapsed/refractory multiple myeloma."

"The initial results of bb21217 are encouraging in terms of the adverse event profile, as well as the instances of ongoing, deep responses shown in these heavily pre-treated patients," said Alise Reicin, M.D., President, Global Clinical Development for Celgene. "We look forward to further results from this next-generation agent in this area of continued medical need."

bb21217 is being evaluated in the ongoing dose escalation part of the Phase 1 CRB-402 study in adults with relapsed/refractory multiple myeloma who have received at least three prior treatments, including a proteasome inhibitor and immunomodulatory agent (or are double refractory).

"Patients with multiple myeloma often undergo multiple cycles of treatment because there is currently no known cure for this aggressive cancer," said Nina Shah, M.D., University of California, San Francisco, San Francisco, Calif. "The early clinical data from this Phase 1 study show manageable safety findings, and most patients in this initial group achieved an objective response. Future study is needed to assess durability of response at the current dose, as well as safety and activity at higher doses of bb21217."

Patients included in these preliminary Phase 1 results (n=12) had a median age of 63 years (min; max: 44 – 69 years). They had received a median of seven prior lines of therapy (min; max: 4 – 17 lines) and 83 percent of patients received a prior autologous stem cell transplant. Fifty-eight percent (n=7) of patients had high-risk cytogenetics.

All treated patients received a dose of 150 x 106 CAR+ T cells. The median follow-up after bb21217 infusion was 26 weeks (min; max: 4 – 51 weeks). The primary endpoint is safety measured by frequency of adverse events (AEs), dose limiting toxicity (DLT) and changes in laboratory results. Secondary endpoints include disease specific response criteria based on the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma.

Safety Results

The safety results, reported as of the data extract of October 18, 2018, were manageable and consistent with known toxicities of CAR T therapies.

Eight of the 12 patients (67 percent) treated with bb21217 developed cytokine release syndrome (CRS); four Grade 1, three Grade 2, one Grade 3 case and no Grade 4 cases. Additionally, three of the 12 patients (25 percent) experienced neurotoxicity, including one Grade 1, one Grade 2 and one Grade 4 case. All CRS and neurotoxicity events resolved and no deaths occurred on study. Following the Grade 4 neurotoxicity event, patients were divided into two groups based on tumor burden and dosing continued at 150 x 106 CAR+ T cells for a total of 12 subjects treated at this dose level.

Efficacy Results

Of the 12 patients who received treatment with bb21217, 83 percent (n=10) achieved an objective clinical response by IMWG criteria. As of the data extract, responses are ongoing in nine of 10 patients, including three with a complete response (CR) or stringent complete response (sCR), two with a very good partial response (VGPR) and four with a partial response (PR).

Evidence of myeloma in the bone marrow, known as minimal residual disease (MRD), was undetectable at a minimum of two time points, by next-generation sequencing at a sensitivity level of 10-5 or better in all responders who had evaluable bone marrow samples (n=4) with some as early as day 15.

CAR+ T cell expansion was observed during the first 30 days following treatment in all evaluable patients (n=11) with anti-BCMA CAR+T cells showing sustained persistence in all patients (3/3) with six or more months of follow-up.

The ongoing Phase 1 CRB-402 study is assessing a higher dose of 300 x106 CAR+ T cells in both high and low tumor burden cohorts.

About bb21217

bb2121 and bb21217 are bluebird bio’s lead investigational anti-BCMA CAR T therapies being developed in collaboration with Celgene.

Chimeric antigen receptors (CAR) are receptor proteins that have been engineered to give T cells the ability to target a specific protein. bb2121 and bb21217 are designed to recognize and kill plasma cells, notably malignant myeloma cells, that express the B cell maturation antigen (BCMA).

bluebird bio’s clinical development program for bb21217 includes the ongoing Phase 1 CRB-402 two-part (dose escalation and dose expansion), non-randomized, open label study with sites in the United States. For more information visit: clinicaltrials.gov using identifier NCT03274219.

bb21217 is not approved for any indication in any geography.

About Multiple Myeloma

Multiple myeloma is a cancer of certain cells in the blood, called plasma cells. The cause of multiple myeloma is not known, and currently there is no cure. However, there are a number of treatment options available that can lead to remission. For some people with multiple myeloma, remission can last many years. Patients who have already been treated with some available therapies but continue to have progression of their disease have "relapsed" or "refractory" multiple myeloma, meaning their cancer has reoccurred after they have received initial treatments. Patients with relapsed/refractory multiple myeloma have fewer treatment options.

On December 2, 2018 Pfizer Inc. (NYSE:PFE) reported at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting that the REFLECTIONS B328-06 study, a comparative safety and efficacy study of PF-05280586 versus Rituxan/MabThera (rituximab-EU)i, met its primary endpoint of overall response rate (ORR) at Week 26 of the 52-week study.1

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"It is encouraging to see new data supporting a potential rituximab Biosimilar. If approved this may help provide a more cost-effective treatment option and expand access for patients and physicians," said Dr. Jeff Sharman, medical director, US Oncology Hematology Research. "The data presented today will help us understand the nuances of the medicine without the confounding influence of additional concurrent treatments."

26-week data from the ongoing 52-week REFLECTIONS B328-06 study (n=394) demonstrated no clinically meaningful differences in efficacy, in terms of ORR at Week 26, between PF-05280586 and MabThera, for the first-line treatment of patients with CD20-positive, low tumor burden, follicular lymphoma (LTB-FL).1 ORR at Week 26 was 75.5% (PF-05280586) vs 70.7% (rituximab-EU), and was within the pre-specified equivalence margin. ORR is defined as the percentage of patients achieving complete response (CR) or partial response (PR), based on central review. Additionally, estimated rates of one-year progression-free survival were similar across groups (76.4% vs. 81.2% in the PF-05280586 and MabThera groups, respectively).1 The results also show that PF-05280586 had a similar safety profile to MabThera.1

"With a patient centered approach and over a decade of experience globally,2 Pfizer remains dedicated to developing and delivering high quality biosimilars with similar efficacy and safety profiles to originator medicines that help have a meaningful impact on people living with various conditions including cancer," said Joe McClellan, vice president, Biosimilars Development at Pfizer. "We have also been a committed global partner to the oncology community for almost 20 years, and the continued growth of our oncology and supportive care presence, through both novel therapies and biosimilars, means we are able to provide patients, physicians and healthcare systems with a wider range of treatment options."

PF-05280586 has been accepted for review by the FDA, the BsUFA goal date for a decision by the FDA is in second-quarter 2019. Pfizer is also working towards making PF-05280586 available for patients in Europe. Further results on the safety and efficacy from this ongoing 52-week study in LTB-FL are expected to be presented next year.

About PF-05280586

PF-05280586 is a monoclonal antibody (mAb) that is in development as a potential biosimilar to Rituxan/MabThera. Rituxan/MabThera is indicated for the treatment of patients with certain types of CD20-positive non-Hodgkin lymphoma; CD20-positive chronic lymphocytic leukemia; rheumatoid arthritis; granulomatosis with polyangiitis and microscopic polyangiitis; and other region-specific indications.3, 4

PF-05280586 is an investigational compound and has not received regulatory approval in any country. Biosimilarity has not yet been established by regulatory authorities.

About the REFLECTIONS B328-06 Study

REFLECTIONS B328-06 is a randomized, 52-week double-blind clinical trial evaluating the efficacy, safety and immunogenicity, pharmacokinetics and pharmodynamics of PF-05280586 versus MabThera for the first-line treatment of patients with CD20-positive, low tumor burden, follicular lymphoma.

More information about the PF-05280586 REFLECTIONS B32806 study can be found at www.clinicaltrials.gov.

On December 2, 2018 Syros Pharmaceuticals (NASDAQ: SYRS), a leader in the development of medicines that control the expression of genes, reported initial clinical data from cohorts in its ongoing Phase 2 trial evaluating SY-1425, its first-in-class selective retinoic acid receptor alpha (RARα) agonist, in combination with azacitidine and with daratumumab in genomically defined patients with acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (MDS) (Press release, Syros Pharmaceuticals, DEC 2, 2018, View Source [SID1234531794]). These data are being presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

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"AML and MDS are complex diseases, and we need therapies that can be used in combination to help patients live longer and with a better quality of life," said Rachel J. Cook, M.D., M.S., Assistant Professor of Medicine and Site Director for Acute Leukemia at the Knight Cancer Institute, Oregon Health and Science University and a clinical investigator in the Phase 2 study of SY-1425. "These data provide early clinical evidence that SY-1425 may be a meaningful treatment option for defined subsets of AML and MDS patients that is generally well-tolerated in combination with other therapies. I look forward to continuing to investigate SY-1425 to fully understand its potential to benefit patients."

"These initial combination data from our ongoing Phase 2 trial of SY-1425 are promising," said David A. Roth, M.D., Syros Chief Medical Officer. "SY-1425 in combination with azacitidine showed both a high response rate and rapid onset of clinical responses in AML patients selected with our RARA or IRF8 biomarkers that we have not seen to date in the biomarker-negative cohort. The combination was generally well-tolerated with no evidence of increased toxicities beyond what would be expected with each agent alone, including myelosuppression that can sometimes be seen when combining drugs to treat leukemia. These data speak to the combination potential of SY-1425 as well as to the potential of our platform to identify patients most likely to respond to gene control medicines. We look forward to further characterizing the clinical activity of SY-1425 in combination with azacitidine as we continue to enroll and follow patients in the trial."

SY-1425 in Combination with Azacitidine
The ongoing Phase 2 trial cohort is evaluating the safety and efficacy of SY-1425 in combination with azacitidine, a standard-of-care hypomethylating agent, in RARA or IRF8 biomarker-positive patients with newly diagnosed AML who are not suitable candidates for standard chemotherapy. The trial also includes a cohort evaluating SY-1425 in combination with azacitidine in biomarker-negative newly diagnosed, unfit AML patients, with the aim of supporting the development of a commercial companion diagnostic. Patients in these cohorts were treated with azacitidine administered at standard daily doses of 75 mg/m2 intravenously or subcutaneously for seven days, followed by SY-1425 administered at 6 mg/m2 orally divided in two daily doses for the remainder of the 28-day cycle.

As of Oct. 29, 2018, 11 biomarker-positive and eight biomarker-negative patients had been enrolled in the trial. Of the biomarker-positive patients, 10 were evaluable for safety and eight were also evaluable for clinical responses. Of the biomarker-negative patients, seven were evaluable for safety and six were also evaluable for clinical responses. The median age of the biomarker-positive patients was 76 and the median age of the biomarker-negative patients was 78, with more than half the patients in both cohorts having poor risk cytogenetics. Target enrollment in both the biomarker-positive cohort and the biomarker-negative cohort is 25, and Syros continues to enroll and follow patients.

Initial Safety Data

SY-1425 in combination with azacitidine was generally well-tolerated with no evidence of increased toxicities.
Adverse events (AEs) were consistent with what has been previously seen with SY-1425 or azacitidine as single agents in AML:
Across all grades and causalities, the most commonly reported AEs were decreased appetite (41%), fatigue (35%) and hypertriglyceridemia (35%).
The most commonly reported Grade 3 or higher AEs (all causality) were febrile neutropenia (24%), thrombocytopenia (24%), neutropenia (12%) and fatigue (12%).
Initial Clinical Activity Data

The complete response (CR) and complete response with incomplete blood count recovery (CRi) rate, as defined by Revised International Working Group (IWG) criteria, was 50% in the biomarker-positive cohort.
The overall response rate (ORR), using IWG criteria, was 63%, consisting of:
Three CRs, including one molecular CR.
One CRi.
One morphologic leukemia-free state (MLFS).
Duration of these IWG responses ranged from 29 to 337 days, with four of the five responding patients remaining on treatment as of the data cutoff.
Most of the initial responses were seen at the end of the first treatment cycle.
These data compare favorably to single-agent azacitidine, which shows response rates of 18-29% in newly diagnosed unfit AML patients1 with initial responses generally occurring after four cycles of treatment in most patients who respond2.
In the cohort of biomarker-negative patients, the ORR was 17%, with one of the six response-evaluable patients achieving a cytogenetic CR. While data from this cohort are less mature, the difference in the observed ORR supports the potential predictive value of the RARA and IRF8 biomarkers for identifying patients most likely to respond to SY-1425.
SY-1425 in Combination with Daratumumab
The ongoing Phase 2 trial is characterizing CD38 induction with SY-1425 and evaluating the safety and efficacy of SY-1425 in combination with daratumumab in a pilot cohort of 12 RARA or IRF8 biomarker-positive patients with relapsed or refractory AML or higher-risk MDS. Daratumumab is an anti-CD38 targeted therapy that is approved to treat multiple myeloma. While CD38 is normally expressed at high levels on multiple myeloma cells, AML cells have low CD38 expression. In preclinical studies, SY-1425 induced CD38 expression in AML cells, sensitizing them to treatment with daratumumab. Patients in this cohort were treated with SY-1425 as a single agent administered at 6 mg/m2 orally, divided in two daily doses, for seven days, after which daratumumab was added and administered at 16 mg/kg intravenously weekly for eight doses, then biweekly for eight doses and every four weeks thereafter.

As of Oct. 29, 2018, nine patients had been enrolled in this cohort. All nine were evaluable for safety and CD38 induction, and six were also evaluable for clinical responses. The median age of these patients was 68, with more than half having poor risk cytogenetics. Syros continues to enroll patients to complete the pilot.

Initial Safety Data

SY-1425 in combination with daratumumab was generally well-tolerated with no evidence of increased toxicities.
AEs were consistent with what has been previously seen with single-agent SY-1425 in AML and MDS patients or single-agent daratumumab in multiple myeloma patients:
Across all grades and causalities, the most commonly reported AEs were febrile neutropenia (67%), anemia (44%), nausea (44%), vomiting (44%) and infusion-related reaction (44%).
The most commonly reported Grade 3 or higher AEs (all causality) were febrile neutropenia (67%) and anemia (44%).
Initial CD38 Induction and Clinical Activity Data

Eight of the nine patients had increased CD38 expression in myeloid blast cells, with a median 1.57-fold induction as measured by mean fluorescence intensity (MFI), after seven days of treatment with SY-1425.
CD38 expression increased in only two of these patients to levels exceeding those of a multiple myeloma cell line control:
One had an MLFS response.
The other progressed without a clinical response.
The initial clinical data on both combinations presented at the ASH (Free ASH Whitepaper) meeting is now available on the Publications and Abstracts section of the Syros website at www.syros.com.

Additional details about the Phase 2 trial of SY-1425 can be found using the identifier NCT02807558 at www.clinicaltrials.gov.