On December 2, 2018 Aprea Therapeutics reported results at the 2018 ASH (Free ASH Whitepaper) Annual Meeting from its Phase Ib/II clinical study in MDS (Press release, Aprea, DEC 2, 2018, View Source [SID1234531805]). The ongoing study is evaluating the safety and efficacy of APR-246 in combination with azacitidine for the treatment of TP53 mutated MDS. The study is sponsored by the Moffitt Cancer Center with financial support from the MDS Foundation and the Aplastic Anemia and MDS International Foundation as administrator for the Evans MDS Clinical Research Consortium.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The overall response rate in 20 evaluable patients was 95%, with 14 (70%) patients achieving a complete remission (CR) at data cutoff. Relative to baseline, p53 immunohistochemistry positivity, mutant TP53 variant allele frequency (VAF) and TP53 minimal residual disease (MRD) were significantly decreased at time of disease assessment. No dose-limiting toxicities have been experienced to date and no exacerbation of the expected AZA-related safety profile has been observed.

"The expanding data set from this study is very encouraging," said David Sallman, M.D., lead principal investigator of the clinical study from the Moffitt Cancer Center. "As of this latest data cutoff, responses have been achieved in nearly all patients, including a 70% complete remission rate, and accompanied by deep molecular remission in the majority of patients as assessed by serial TP53 analysis. In addition, the overall safety experience indicates that the combination regimen of APR-246 and azacitidine is both safe and well-tolerated. Comparison of the current data set to historical AZA clinical experience suggests that combination of APR-246 with AZA may offer these patients a better potential treatment option than AZA alone."

"The continued positive data from this clinical study has created the potential for a new treatment paradigm for patients with few therapeutic options," said Christian S. Schade, President and Chief Executive Officer of Aprea. "As a result of this exciting progress, Aprea expects to soon begin enrolling a randomized, controlled Phase III clinical study of APR-246 in combination with AZA for the treatment of TP53 mutated MDS."

About the Clinical Study

Eligible patients in the Phase Ib/II clinical study include HMA naïve, TP53 mutated MDS and oligoblastic acute myeloid leukemia (AML, ≤ 30% blasts). In the Phase Ib part of the clincal study, patients received APR-246 in a 3+3 dose escalation design (50, 75, 100 mg/kg lean body weight) IV daily over 4 days in a lead-in phase (days -14 to -10), followed by the same dose of APR-246 (days 1-4) and AZA 75 mg/m2 SC/IV over 7 days (days 4-10 or 4-5 and 8-12) in 28-day cycles. In the Phase II part of the clinical study, patients receive APR-246 as a 4,500 mg fixed dose IV daily (days 1-4) and AZA over 7 days (days 4-10 or 4-5 and 8-12) in 28-day cycles. Primary objective in Phase Ib part of the clinical study was safety, with AEs graded by CTCAE v4.03 and DLT assessment over 6 weeks. Secondary endpoints included response rate by IWG 2006 criteria, PFS, OS, as well as serial next generation sequencing and p53 immunohistochemistry for evaluation of clonal suppression and depth of remission. In the Phase II part of the clinical study the primary endpoint is response rate.

About Myelodysplastic Syndrome

Myelodysplastic syndromes (MDS) represents a spectrum of hematopoietic stem cell malignancies in which bone marrow fails to produce sufficient numbers of healthy blood cells. Approximately 30-40% of MDS patients progress to acute myeloid leukemia (AML) and mutation of the p53 tumor suppressor protein is thought to contribute to disease progression. Mutations in p53 are found in up to 20% of MDS and AML patients and are associated with poor overall prognosis.

About p53 and APR-246

The p53 tumor suppressor gene is the most frequently mutated gene in human cancer, occurring in approximately 50% of all human tumors. These mutations are often associated with resistance to anti-cancer drugs and poor overall survival, representing a major unmet medical need in the treatment of cancer.

APR-246 has been shown to reactivate mutant and inactivated p53 protein – by restoring wild-type p53 conformation and function – and thereby induce programmed cell death in human cancer cells. APR-246 has demonstrated pre-clinical anti-tumor activity in a wide variety of solid and hematological (blood) tumors, including MDS, AML, and ovarian cancer, among others. Additionally, strong synergy has been seen with both traditional anti-cancer agents, such as chemotherapy, as well as newer mechanism-based anti-cancer drugs and immuno-oncology checkpoint inhibitors. In addition to pre-clinical testing, a Phase I/II clinical program with APR-246 has been completed, demonstrating a favorable safety profile and both biological and confirmed clinical responses in hematological malignancies and solid tumors with mutations in the TP53 gene.

On December 2, 2018 Celgene Corporation (NASDAQ: CELG) and Acceleron Pharma Inc. (NASDAQ: XLRN) reported results from the pivotal, phase 3 MEDALIST trial evaluating the efficacy and safety of investigational luspatercept to treat patients with ring sideroblast (RS+) myelodysplastic syndromes (MDS)-associated anemia who require red blood cell transfusions and who had failed, were intolerant to, or ineligible for erythropoietin therapy (Press release, Celgene, DEC 2, 2018, View Source [SID1234531801]). Results were presented by Alan F. List, M.D. during the Plenary Scientific Session at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, C.A. (Abstract #1).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Severe anemia resulting in red blood cell transfusion dependence is a significant challenge for patients with low- and intermediate-risk MDS. Those who become resistant or refractory to currently available treatments have limited alternatives," said Dr. List, President and CEO of Moffitt Cancer Center. "The findings from MEDALIST are very exciting as they support the hypothesis that targeting red blood cell precursor maturation could help to address patients’ anemia and allow them to achieve transfusion independence."

MEDALIST met the primary endpoint of red blood cell transfusion independence (RBC-TI) for 8 or more weeks during the first 24 weeks of the study. Treatment with luspatercept resulted in a statistically significantly greater proportion of patients achieving RBC-TI ≥ 8 weeks compared to placebo. The study also found in secondary endpoints that treatment with luspatercept resulted in a statistically significant higher percentage of patients achieving RBC-TI of 12 or more weeks in the first 24 or 48 weeks of the study, as well as hematologic improvement-erythroid (HI-E) of 8 or more weeks.

Endpoints Luspatercept Placebo P-Value
RBC-TI ≥8 weeks (weeks 1-24) 37.9 % (58/153) 13.2 % (10/76) < 0.0001
RBC-TI ≥12 weeks (weeks 1-24) 28.1 % (43/153) 7.9 % (6/76) 0.0002
RBC-TI ≥12 weeks (weeks 1-48) 33.3 % (51/153) 11.8 % (9/76) 0.0003
HI-E ≥ 8 weeks (IWG 2006, weeks 1-24) 52.9 % (81/153) 11.8 % (9/76) < 0.0001

MEDALIST Safety Summary

Treatment-emergent adverse events (TEAEs) of Grade 3 or 4 were reported in 42.5% (65/153) of patients receiving luspatercept and 44.7% (34/76) of patients receiving placebo. Progression to acute myeloid leukemia (AML) occurred in four patients, three patients (2.0%) receiving luspatercept and one patient (1.3%) receiving placebo. Five patients receiving luspatercept (3.3%) and four patients receiving placebo (5.3%) experienced one or more TEAE that resulted in death.

Most common TEAEs of any Grade in Greater than 10% of Patients in Either Arm

Luspatercept
N=153

Placebo
N=76

Fatigue 26.8 % 13.2 %
Diarrhea 22.2 % 9.2 %
Asthenia 20.3 % 11.8 %
Nausea 20.3 % 7.9 %
Dizziness 19.6 % 5.3 %
Back pain 19.0 % 6.6 %

"The MEDALIST results demonstrate the potential clinical benefit of luspatercept in achieving red blood cell transfusion independence in patients with low-to-intermediate risk RS+ MDS, an area in need of new treatments," said Alise Reicin, MD, President, Global Clinical Development for Celgene. "Based on these results, we are encouraged that this first-in-class erythroid maturation agent may help these patients address the underlying cause of their disease-related chronic anemia."

"It’s truly an honor to showcase the results from the MEDALIST trial as the first presentation of the ASH (Free ASH Whitepaper) Plenary Session," said Habib Dable, President and Chief Executive Officer of Acceleron. "The results from the MEDALIST trial increase our confidence in the potential of luspatercept to provide a meaningful treatment option for patients suffering from lower-risk RS+ MDS worldwide. We’re excited to continue our clinical development program in MDS, beta-thalassemia, and myelofibrosis, while also exploring additional applications for luspatercept in a range of diseases associated with anemia."

Luspatercept is not approved in any region for any indication. The companies are planning regulatory application submissions of luspatercept in the United States and Europe in the first half of 2019.

About MEDALIST

MEDALIST is a phase 3, randomized, double blind, placebo-controlled, multi-center study evaluating the safety and efficacy of luspatercept in patients with very low-, low-, or intermediate-risk non-del(5q) myelodysplastic syndromes (MDS). All patients were RBC transfusion dependent and were either refractory or intolerant to prior erythropoiesis-stimulating agent (ESA) therapy, or were ESA naïve with endogenous serum erythropoietin ≥ 200 U/L, and had no prior treatment with disease modifying agents. The median age of the patients enrolled in the trial was 71 years in the luspatercept treatment group and 72 years in the placebo group. Median transfusion burden in both treatment arms was 5 RBC units/8 weeks. 229 patients were randomized to receive either luspatercept 1.0 mg/kg (153 patients) or placebo (76 patients) via subcutaneous injection once every 21 days. The study was conducted at 65 sites in 11 countries.

About Luspatercept

Luspatercept is a first-in-class erythroid maturation agent (EMA) that is believed to regulate late-stage red blood cell maturation. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. Phase 3 clinical trials continue to evaluate the safety and efficacy of luspatercept in patients with MDS (the MEDALIST trial) and in patients with beta-thalassemia (the BELIEVE trial). The COMMANDS phase 3 trial in first-line, lower-risk, MDS patients, the BEYOND phase 2 trial in non-transfusion-dependent beta-thalassemia, and a phase 2 trial in myelofibrosis are ongoing. For more information, please visit www.clinicaltrials.gov.

On December 2, 2018 Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company focused on the development of precision medicines for oncology, reported preliminary data in angioimmunoblastic T-cell lymphoma (AITL) and CXCL12+ peripheral T-cell lymphoma (PTCL), the two expansion cohorts in its Phase 2 clinical trial of its lead drug candidate tipifarnib in patients with relapsed or refractory PTCL (Press release, Kura Oncology, DEC 2, 2018, View Source [SID1234531800]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The data, presented today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, showed encouraging activity with tipifarnib in late-stage PTCL patients, including a significant association between CXCL12 expression and clinical benefit, and proof of concept in AITL, an aggressive form of T-cell lymphoma often characterized by high levels of CXCL12 expression. A copy of the poster is available on the Company’s website at www.kuraoncology.com.

"The mechanism of action of farnesyl transferase inhibitors has remained elusive for several decades," said Antonio Gualberto, M.D., Ph.D., Head of Development and Chief Medical Officer of Kura Oncology. "Our initial data in HRAS mutant head and neck cancer provided strong evidence of activity in tumors driven by this oncogene. However, many other tumors such as T- and B-cell lymphomas, myeloid leukemias, pancreatic or breast cancers, in which anecdotal evidence of tipifarnib activity has been reported, do not usually carry HRAS mutations. We believe the preliminary results reported at ASH (Free ASH Whitepaper) validate our observation that the CXCL12 pathway is a therapeutic target of tipifarnib and provide a potential path to expand the development of tipifarnib well beyond HRAS mutant solid tumors by using CXCL12-related biomarkers to enrich for patients most likely to benefit from treatment. We will continue our efforts to identify these patient subsets and to bring this important drug candidate to patients in need."

As of November 21, 2018, a total of 39 patients were enrolled in the ongoing Phase 2 trial, including 19 patients with AITL (16 patients in the AITL extension cohort and 3 patients in the previous portion of the study). Six of the 16 AITL patients were not evaluable as of the data cutoff date, including two who were pending initial efficacy assessments. Of the 13 evaluable AITL patients, two achieved a complete response (CR) and four achieved a partial response (PR), for an objective response rate (ORR) of 46% (six of 13). According to the study protocol, the AITL cohort is considered positive when four or more responses are observed.

The study also identified a particularly responsive subset within AITL and non-AITL patients. Specifically, patients with a high ratio of expression of CXCL12 to its receptor CXCR4 experienced a 50% ORR (five of 10) and a 90% clinical benefit rate (nine of 10 with either complete response, partial response or stable disease) with tipifarnib. Patients in this Phase 2 trial had a median of three prior lines of therapy (range 1-7). The high CXCL12/CXCR4 expression ratio had 90% sensitivity and 93% specificity to identify PTCL patients likely to benefit from tipifarnib.

In addition to the Phase 2 clinical data, the results from two ancillary, non-clinical studies were also reported at ASH (Free ASH Whitepaper). In the first, the expression of CXCL12 and CXCR4 was investigated using tumor bank samples of PTCL patients treated with standard-of-care agents. Worse prognosis was observed in PTCL patients with high CXCL12/CXCR4 expression ratio, indicating that CXCL12 is a negative prognostic factor for standard PTCL therapy. In the second study, the effect of the incubation of stroma cells with tipifarnib on CXCL12 secretion was investigated in a mouse model of bone marrow culture. Tipifarnib reduced secretion of the CXCL12 chemokine from the stromal cells, providing a potential mechanism of action for the observed clinical activity.

"To our knowledge, these results position tipifarnib as the first CXCL12 inhibitor with reported proof-of-concept data, marking a significant advancement in our development strategy," said Troy Wilson, Ph.D., President and CEO of Kura Oncology. "Our data suggest that as many as 40% of PTCL patients express high CXCL12. In addition, the discovery of CXCL12-related biomarkers offers the potential to increase the opportunity for tipifarnib into other hematological and solid tumor indications. We intend to explore those indications while continuing to gather additional data from our ongoing Phase 2 study and expect to provide an update at a medical meeting next year."

The Phase 2 study was designed to investigate the anti-tumor activity of tipifarnib in patients with relapsed or refractory PTCL. After preliminary data suggested that CXCL12 expression was associated with tipifarnib’s clinical activity, two expansion cohorts were added to enroll patients with tumors expected to overexpress CXCL12: AITL tumors, and those non-AITL tumors that lack a single nucleotide variation in the 3’-untranslated region (3′-UTR) of the CXCL12 gene (CXCL12+ PTCL). CXCL12 is a stroma-derived chemokine that promotes the progression of lymphoma and other hematological and solid tumors carrying the CXCR4 receptor, and our previous results had suggested an association between CXCL12 expression and the most common form of the 3’-UTR CXCL12 variant. In the expansion cohorts, both the presence or absence of this variant and the expression levels of CXCL12 and CXCR4 were assessed.

In the expansion cohorts in the Phase 2 trial tipifarnib was dosed at 300 mg twice daily on days 1-21 of a 28-day cycle. The reported data indicated that tipifarnib was generally well-tolerated, with adverse events consistent with its known safety profile. The most common treatment-related adverse events (grade ≥ 3) were hematology-related, including neutropenia, thrombocytopenia, leukopenia, febrile neutropenia and anemia.

Last week, the U.S. Patent and Trademark Office (USPTO) issued a new patent for tipifarnib as a method of treating patients with AITL. In May 2018, the USPTO issued a patent for tipifarnib as a method of treating patients with certain CXCL12-expressing cancers, including PTCL. Both patents expand protection for tipifarnib, providing exclusivity in the U.S. to 2037.

Webcast Information

Kura’s management will host a webcast at 11:30 p.m. ET / 8:30 p.m. PT today, December 2, 2018, following the conclusion of the poster presentation at the ASH (Free ASH Whitepaper) 2018 Annual Meeting. The live audio webcast and slides of the presentation will be available from the Investors and Media section of the company website at www.kuraoncology.com, and will be archived there for 30 days.

About Tipifarnib

Kura Oncology’s lead drug candidate, tipifarnib, is a potent and highly selective inhibitor of farnesylation, a key cell signaling process implicated in cancer initiation and development. Tipifarnib was previously studied in more than 5,000 cancer patients and showed compelling and durable anti-cancer activity in certain patient subsets, however no molecular mechanism of action had previously been determined that could explain its activity across a range of diverse clinical indications, including squamous tumors that carry mutant HRAS, as well as in lymphoid, myeloid and solid tumors that do not carry HRAS mutations. Leveraging advances in next-generation sequencing as well as emerging information about cancer genetics and tumor biology, Kura is seeking to identify those patients most likely to benefit from tipifarnib. In November 2018, Kura initiated its first global, registration-directed trial of tipifarnib in patients with recurrent or metastatic HRAS mutant HNSCC

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]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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