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Immune Design Reports Increased Overall Response Rate and Longer Progression Free Survival of Patients with Follicular Lymphoma Treated in a Randomized Trial with a Combination Regimen of G100 and Pembrolizumab

On December 2, 2018 Immune Design (Nasdaq: IMDZ), an immunotherapy company focused on next-generation therapies in oncology, reported long-term follow up results from a randomized Phase 2 clinical trial of 10 ug intratumoral G100, a TLR4 agonist, with or without pembrolizumab, in follicular lymphoma patients (Press release, Immune Design, DEC 2, 2018, View Source [SID1234531785]).

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In the 26 naïve and relapsed/refractory patients in the randomized trial, the data continue to support the clinical activity of G100, with overall response rates of 46% and 23% in patients receiving a G100 regimen that includes low-dose radiation, with or without pembrolizumab, respectively. Also, disease control was shown in 92% and 85% of patients treated with the G100 regimen with or without pembrolizumab, respectively. In addition, responses appeared to be durable, with overall progression free survival at 11.1 or 7.4 months in patients treated with the G100 regimen with or without pembrolizumab, respectively. The data were presented today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held in San Diego.

"Follicular lymphoma continues to be a difficult-to-treat malignancy, particularly in the relapsed setting, and to date immunotherapy has not been successful and the current standard of care is associated with a number of serious adverse events," said Carlos Paya, M.D., chief executive officer of Immune Design. "We are encouraged by the potential for lymphoma patients with G100, a first in class immuno-modulatory agent that leads to systemic anti-lymphoma benefit when injected intratumorally. The high response rates, favorable durability and excellent safety profile we’re seeing for G100 has prompted us to embark on a potentially pivotal clinical trial in the relapsed refractory setting, as well as pursue additional trials in earlier lines of therapy in follicular lymphoma and other malignancies."

Additional data presented in the poster:

Increases in immunogenicity markers of CD8+ T-cells and CD8/CD4 ratio in the tumor microenvironment correlated with clinical response (p= .0858 and .0357 respectively). Similarly, a decrease in C20-expressing tumor cells correlated with improved clinical outcomes (p=.0221).

G100 was well tolerated and the combination with pembrolizumab did not cause unexpected or worsening toxicity.
About G100

G100 is Immune Design’s lead product candidate and contains a potent synthetic small molecule toll-like receptor-4 (TLR-4) agonist called Glucopyranosyl Lipid A (GLA). G100 activates innate and adaptive immunity in the tumor microenvironment to generate an immune response against the tumor’s pre-existing diverse set of antigens. A growing set of clinical and preclinical data have demonstrated the ability of G100 to activate tumor-infiltrating lymphocytes, macrophages and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor. The induction of local and systemic immune responses has been shown to result in local and abscopal (shrinking of tumors outside the scope of the localized treatment) tumor control. G100 is currently in development to treat patients with relapsed follicular lymphoma (FL), a sub-type of Non-Hodgkin lymphoma. Immune Design intends to start a study in earlier-stage lymphoma patients in combination with rituximab, a standard treatment for lymphomas, and is evaluating studies in other B-cell malignancies beyond FL, as well as potential solid tumor indications.

Celgene Corporation Announces Initial Phase 1/2 Liso-cel Data in Patients with Relapsed/Refractory CLL, Including Those with High-Risk Disease, Previously Treated with Ibrutinib, at ASH 2018

On December 2, 2018 Celgene Corporation (NASDAQ: CELG) reported initial data from the dose-escalation part of an ongoing, open-label multicenter phase 1/2 study of investigational lisocabtagene maraleucel (liso-cel; JCAR017) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), including patients with cytogenetic features of high-risk disease, who were previously treated with ibrutinib (Press release, Celgene, DEC 2, 2018, View Source [SID1234531784]). The data were presented by Tanya Siddiqi, 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 #300).

Data presented today from TRANSCEND CLL-004 include 16 patients from the ongoing phase 1 monotherapy dose-escalation part of the study. The median number of lines of prior therapy was 4.5, and 75% of patients had high-risk cytogenetic features. All patients had previously received treatment with ibrutinib, 81% had relapse/refractory disease on ibrutinib and 50% received prior treatment with ibrutinib and venetoclax. Following lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) for three days, patients received liso-cel at dose level 1 (5×107 CAR+ T cells) or dose level 2 (1×108 CAR+ T cells).

The overall response rate (ORR), which was an exploratory objective, was 81%, with 43% of patients demonstrating a complete response (CR). As of September 2018, five patients have six-month follow-up and all have maintained a response and undetectable minimal residual disease (uMRD) in the blood as measured by flow cytometry (10-4). The median time-to-peak expansion was 16 days, and CAR+ T cells remained detectable in patients at three months.

"Ibrutinib is a standard of care for patients with CLL, but outcomes are poor for patients whose disease progresses on or after ibrutinib," said Alise Reicin, M.D., President, Global Clinical Development for Celgene. "These initial findings support further research with liso-cel in CLL and reinforce Celgene’s commitment to cellular therapy across a broad spectrum of blood cancers."

The most common treatment-emergent adverse events reported included anemia (88%), thrombocytopenia (81%), cytokine release syndrome (75%), neutropenia (63%), leukopenia (56%), hypokalemia (50%), pyrexia (38%), lymphopenia (31%), nausea (31%), diarrhea (25%), febrile neutropenia (25%), headache (25%), insomnia (25%), and tremor (25%). One patient (6.3%) experienced grade 3 cytokine release syndrome and three patients (18.8%) experienced grade 3 neurologic events. No patients experienced grade 4 cytokine release syndrome or neurologic events.

"In CLL, undetectable MRD correlates with improved outcomes for patients and is particularly difficult to achieve in patients who have progressed on ibrutinib," said lead study investigator Tanya Siddiqi, M.D., City of Hope National Medical Center. "The high response rates we observed in heavily pretreated patients in this initial data set, along with undetectable MRD status, that appears to be maintained over time, warrants further investigation of liso-cel in this area of high unmet need."

Liso-cel is not approved in any country.

About Liso-cel

Liso-cel is an investigational defined composition CD19-directed CAR T cell product candidate using a 4-1BB costimulatory domain. Celgene’s lead CAR T trial, TRANSCEND NHL-001, is studying liso-cel in adult patients with relapsed or refractory diffuse large B cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma Grade 3B, and mantle cell lymphoma.

Bellicum Announces Data Presentation at ASH 2018 Demonstrating Low Rates of Cancer Recurrence in Pediatric AML and ALL Patients Treated with Rivo-cel

On December 2, 2018 Bellicum Pharmaceuticals, Inc. (NASDAQ:BLCM), a leader in developing novel, controllable cellular immunotherapies for cancers and orphan inherited blood disorders, reported additional follow-up results from a subset of children with high-risk/relapsed acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) (Press release, Bellicum Pharmaceuticals, DEC 2, 2018, View Source [SID1234531780]). The data showed durable anti-leukemic effects in patients treated with rivo-celTM (rivogenlecleucel, formerly BPX-501) following αβT-cell and B-cell depleted allogeneic hematopoietic stem cell transplantation (HSCT). The data were reviewed in an oral presentation today at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (ASH 2018) by Principal Investigator Franco Locatelli, M.D., Ph.D., Director of the Department of Hematology and Oncology and Cell/Gene Therapy at Ospedale Pediatrico Bambino Gesù in Rome, Italy.

"Cancer recurrence is one of the primary factors affecting the success rate of allogeneic HSCT. Rivo-cel appears to lower the rate of cancer recurrence in children receiving αβT-cell and B-cell depleted allogeneic HSCT—suggesting that the diverse population of donor T cells in rivo-cel product may reduce or eliminate residual cancer cells," said Dr. Locatelli. "Moreover, while you might expect to see Graft versus Host Disease with this approach, the overall rates were low and rimiducid was effective for most patients who developed visceral GvHD or who were refractory to standard of care treatment for GvHD. These encouraging data support the potential of rivo-cel as an important treatment for children with blood cancers who need a stem cell transplant and lack a matched donor."

Study Design and Highlights

Investigators evaluated the safety and efficacy of rivo-cel administered after an αβT-cell and B-cell depleted haploidentical HSCT (haplo-HSCT) in pediatric patients with high-risk/relapsed acute leukemias in morphological complete remission (CR). The objective was to determine whether rivo-cel could extend relapse-free survival (RFS) and overall survival (OS) via graft versus leukemia (GvL) effect, while maintaining a low-risk of GvHD. 100 AML and ALL HSCT patients were evaluated for safety. 95 of 100 patients received rivo-cel treatment and therefore were eligible for efficacy evaluation. Patients had a median follow-up of 17 months. Results are summarized as follows:

Survival outcomes:

ALL
n = 52 AML
n = 43
Relapse-free survival
CR1
CR2

100.0%
73.2%

78.0%
88.8%
Overall Survival
CR1
CR2

100.0%
89.9%

86.7%
95.7%
GvHD outcomes:

21 of 96 evaluable patients developed Grade I-IV acute GvHD (21.9%); 3 patients developed Grade III-IV acute GvHD (3.1% [95% CI: 0 – 6.6%]) 9 cases of late-onset aGVHD occurred after 100 days (2 cases of Grade III) 7 of 89 evaluable patients developed chronic GvHD (10.9% [95% CI: 2.1-19.6%]), with moderate-severe cases in 5 of these patients
Rimiducid treatment outcomes:

Of the 37 patients who developed GvHD, rimiducid was administered to 11 patients Best overall response (within 7 days) was seen in 73% (8 patients); 5 responding patients had a complete response (CR) and 2 patients with a partial response (PR) went on to achieve a complete response within 30 days following rimiducid administration
Commented Rick Fair, President & CEO of Bellicum Pharmaceuticals, "We are extremely pleased by these data, which suggest rivo-cel may be a potent and durable leukemia treatment when added to stem cell transplant. We plan to continue to follow these patients to further evaluate durability. In addition, based on these exciting results, we are in final stages of initiating a global Phase 2/3 trial in patients 12 years and older with AML and myelodysplastic syndromes (MDS) by the end of the year."

A copy of the ASH (Free ASH Whitepaper) presentation will be made available in the Abstracts & Presentations section of the Company’s website.

Analyst and Investor Luncheon Event and Webcast
Bellicum will host a live and webcast analyst and investor luncheon event on December 3, 2018 at 12:00 p.m. – 1:30 p.m. PST in San Diego, CA. Featured speakers include Dr. Alice Bertaina, Associate Professor of Pediatrics, Stem Cell Transplantation, Lucile Packard Children’s Hospital at the Stanford School of Medicine, as well as Bellicum senior management. A webcast replay of the event will be available on the News & Events section of the Bellicum website, and available for at least two weeks following the event.

About Rivo-cel (BPX-501)
Rivo-celTM (rivogenlecleucel) is an allogeneic polyclonal T-cell product designed to accelerate immune recovery after HSCT and to reduce relapse of leukemia following a stem cell transplant. The cell treatment contains a diverse repertoire of T cells which may contribute to a robust graft vs. leukemia effect. Rivo-cel’s antiviral benefits may also reduce morbidity and mortality in patients susceptible to infection following a transplant. The product’s CaspaCIDe safety switch enables this approach by allowing physicians to reduce the number of alloreactive cells in the event of uncontrolled GvHD. Rivo-cel addresses a major unmet need in adult and pediatric leukemia, lymphoma and genetic blood disease patients following a haploidentical stem cell transplant.

NewLink Genetics Presents Encouraging Updated Phase 1 Data with Indoximod Plus Chemotherapy in Frontline AML in an Oral Session at 2018 ASH Annual Meeting

On December 2, 2018 NewLink Genetics Corporation (NASDAQ:NLNK) reported that updated Phase 1 data evaluating indoximod plus standard-of-care chemotherapy for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) were presented today by Ashkan Emadi, MD, PhD, Professor of Medicine and Associate Director for Clinical Research, University of Maryland Greenebaum Comprehensive Cancer Center, in an oral session today at the 60thAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, CA, from 9:30AM – 11:00AM PT, in Grand Hall B, Manchester Grand Hyatt (Press release, NewLink Genetics, DEC 2, 2018, View Source [SID1234531779]).

This Phase 1 trial evaluated the initial safety and preliminary evidence of clinical activity of adding indoximod to standard 7+3 induction and high-dose cytarabine (HiDAC) consolidation chemotherapy for adult patients with newly diagnosed AML. The presentation highlighted an initial safety profile indicating that the treatment regimen was well tolerated with adverse events commensurate with chemotherapy alone. Evidence of clinical activity was observed for indoximod plus chemotherapy in newly diagnosed AML as supported by these Phase 1 data showing post-induction minimal residual disease (MRD) negativity rate of 86% and post-HiDAC1 MRD negativity of 100%.

"These data demonstrate the promising potential for indoximod in combination therapy for patients with newly diagnosed AML and the use of MRD status as a study endpoint," said Dr. Ashkan Emadi. "We remain encouraged and look forward to additional data as this study proceeds."

Fifty-seven patients were screened, and 38 patients initiated induction therapy on protocol. Five patients never received indoximod resulting in an intent-to-treat (ITT) population of 33 patients. Twenty-two patients received the pre-specified 80% of indoximod dosing required to be included in the per protocol (PP) analysis, 8 received less than 80% of the scheduled indoximod dosage, and 3 patients remained on induction treatment as of the date of data cut off. Of these 22 PP patients, 16/22 (73%) achieved complete morphological response (CR) and 6 were primary refractory. Of the patients who achieved CR, 14 had results available from MRD testing post-induction. MRD negativity was defined by a flow cytometry assay at a level of < 0.02% (Hematologics, Inc., Seattle, WA). Of those tested, 12/14 (86%) were MRD-negative. Of the 14 patients, 1 patient proceeded to transplant, and 13 began HiDAC consolidation therapy. Post-HiDAC consolidation, all 13 patients were tested for MRD status with all 13/13 (100%) reported to be MRD-negative. When benchmarked against available published studies, these initial data appear encouraging. For a more precise comparison, a contemporaneous multi-institutional dataset is being aggregated to benchmark these data against data generated from patients undergoing the same chemotherapy regimen without the addition of indoximod using the same MRD assay assessed at the same reference laboratory.

Safety data from this Phase 1 trial indicate that the combination therapy regimen was well tolerated. No RLTs were observed when combining indoximod with standard-of-care chemotherapy. Grade 3 or greater adverse hematologic events included febrile neutropenia, anemia, and thrombocytopenia while non-hematologic events included hypoxia, anemia, and pneumonia. The overall adverse event profile observed in this small sample size is consistent with that of 7+3 induction chemotherapy plus HiDAC consolidation alone.

About AML1,2

Adult acute myeloid leukemia (AML) is a cancer of the blood and bone marrow in which the bone marrow makes abnormal types of white blood cells, red blood cells, or platelets. AML is the most common type of acute leukemia in adults and tends to progress rapidly without treatment. In the US, approximately 19,000 patients per year are diagnosed with AML with only around 25% expected to survive longer than three years. Of those newly diagnosed patients, approximately half are categorized as young and fit for an aggressive chemotherapy treatment regimen.

1National Cancer Institute
2American Society of Clinical Oncology

About Indoximod

Indoximod is an investigational, orally available small molecule targeting the IDO pathway. The IDO pathway is a key immuno-oncology target, suppressing immune response and allowing for immune escape by degrading tryptophan with the resultant production of kynurenine. Indoximod reverses the immunosuppressive effects of low tryptophan and high kynurenine through mechanisms that include modulation of the AhR-driven transcription of genes that control immune function. This results in increased proliferation of effector T cells, increased differentiation into helper T cells rather than regulatory T cells, and downregulation of IDO expression in dendritic cells. Indoximod is being evaluated in combination with treatment regimens including chemotherapy, radiation, checkpoint blockade and cancer vaccines across multiple indications including recurrent pediatric brain tumors, DIPG, and AML.

MorphoSys Presents Updated Data from L-MIND Study of MOR208 plus Lenalidomide in r/r DLBCL at ASH 2018

On December 2, 2018 MorphoSys reported its Updated Data from L-MIND Study of MOR208 in combination with Lenalidomide in r/r DLBCL at ASH (Free ASH Whitepaper) 2018 (Press release, MorphoSys, DEC 2, 2018, View Source [SID1234531777])

MorphoSys AG (FSE: MOR; Prime Standard Segment; MDAX & TecDAX; Nasdaq: MOR) presented data from the ongoing single-arm phase 2 clinical trial known as L-MIND in an oral presentation at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2018 in San Diego, USA. L-MIND is designed to investigate the antibody MOR208 in combination with lenalidomide in patients with relapsed or refractory diffuse large B cell lymphoma (r/r DLBCL) who are not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). MOR208 is an investigational humanized Fc-enhanced monoclonal antibody directed against CD19 and is currently in clinical development in blood cancer indications.

The L-MIND study enrolled patients with r/r DLBCL, who are ineligible for HDC and ASCT, after up to three prior lines of therapy, with at least one prior therapy including an anti-CD20 targeting therapy, such as rituximab. The updated interim data reported today (cut-off date June 5, 2018) included all 81 patients enrolled in the L-MIND trial, with a median observation time of 12 months. Efficacy results in this update are based on assessment by the investigators for all 81 patients. Patients enrolled had a median age of 72 years and had received a median of two prior treatment lines.

The data showed a response in 47 out of 81 patients (overall response rate, or ORR, 58%), with complete responses (CR) in 27 (33%) and partial responses (PR) in 20 (25%) patients. The median progression-free survival (mPFS) was 16.2 months (95% confidence interval (CI) 6.3 months – not reached). Responses were durable with the median duration of response (DoR) not reached (95% CI: NR – NR) and 70% of responding patients were without progression at 12 months (12-month DoR rate: 70%, Kaplan-Meier estimate). A significant proportion of patients (37/81; 46%) were still on study treatment, with 19 having been treated for over 12 months. Median overall survival (OS) was not reached (95% CI: 18.6 months – NR); the 12-month OS rate was 73% (95% CI: 63% – 85%).

Efficacy parameters, such as response rates and median PFS showed comparable results in most patient subgroups of interest, including low/low-intermediate versus intermediate-high/high IPI score, rituximab refractory versus not refractory and primary refractory versus not refractory, amongst others.

No unexpected toxicities were observed for the treatment combination and no infusion-related reactions (IRRs) were reported for MOR208. The most frequent treatment-emergent adverse events (TEAEs) with a toxicity grading of 3 or higher were neutropenia in 35 (43%), thrombocytopenia in 14 (17%), and anemia in 7 (9%) patients each. Treatment-related serious adverse events (SAEs) occurred in 16 (19.8%) patients, the majority of which were infections or neutropenic fever. 41 (50.6%) patients required dose reduction with lenalidomide, 58 patients (72%) could stay on a daily lenalidomide dose of 20 mg or higher.

The results reported today confirm data from earlier interim analyses reported from this trial in March 2018, when 68 patients had been eligible for investigators’ efficacy assessment at the Dec 12, 2017 cut-off date.

"Patients with relapsed or refractory DLBCL who, after having failed initial therapies, are ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT), need more treatment options," commented Dr. Malte Peters, Chief Development Officer of MorphoSys AG. "We are encouraged by our most recent clinical data from the ongoing L-MIND trial. These support our plan to develop MOR208 in combination with lenalidomide, based on our current FDA breakthrough therapy designation, as a potential chemo-free treatment option for this patient population."

Details about the presentation on L-MIND data at ASH (Free ASH Whitepaper) 2018:

Abstract publication number: 227
Session name: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)-Results from Prospective Clinical Trials"
Session date and time: Saturday, December 1, 2018, 4:00pm-5:30pm PST
Presentation time: 5:00pm PST
Room: Marriot Marquis San Diego Marina, Pacific Ballroom 20, San Diego, California.

MorphoSys will hold an investor & analyst event after the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2018 on December 5, 2018, 10:00am EST (3:00pm GMT, 4:00pm CET) in New York. The presentation, a live webcast and a replay of the webcast will be made available at View Source

About DLBCL
Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of malignant lymphoma worldwide and accounts for approximately 30% of all non-Hodgkin lymphomas. Between 30% and 40% of all patients with DLBCL either fail to respond to or show a relapse to initial therapy. Patients who failed frontline therapy and are not eligible to high dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) are reported to have a poor outcome and require more therapeutic options.

About CD19 and MOR208
CD19 is broadly and homogeneously expressed across different B cell malignancies including DLBCL and CLL. CD19 has been reported to enhance B cell receptor (BCR) signaling, which is assumed important for B cell survival, making CD19 a potential target in B cell malignancies.
MOR208 is an investigational humanized Fc-engineered monoclonal antibody directed against CD19. Fc-modification of MOR208 is intended to lead to a significant potentiation of antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), thus aiming to improve a key mechanism of tumor cell killing. MOR208 has been observed in preclinical models to induce direct apoptosis by binding to CD19, which is assumed to be involved in B cell receptor (BCR) signaling.
MorphoSys is clinically investigating MOR208 as a therapeutic option in B cell malignancies in a number of ongoing combination trials. An open-label phase 2 combination trial (L-MIND study) is investigating the safety and efficacy of MOR208 in combination with lenalidomide in patients with relapsed/refractory DLBCL who are not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). Based on interim data from L-MIND, in October 2017 the U.S. FDA granted Breakthrough Therapy Designation for MOR208 plus lenalidomide in this patient population. The pivotal phase 2/3 B-MIND study is designed to investigate MOR208 in combination with the chemotherapeutic agent bendamustine in patients with relapsed/refractory DLBCL who are not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) in comparison to the combination of the anti-CD20 antibody rituximab plus bendamustine. In addition, MOR208 is currently being investigated in patients with relapsed/refractory CLL/SLL after discontinuation of a prior Bruton tyrosine kinase (BTK) inhibitor therapy (e.g. ibrutinib) in combination with idelalisib or venetoclax.