On December 7, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported that updated interim results from an ongoing Phase II clinical trial of Puma’s investigational drug PB272 (neratinib), given as monotherapy and in combination with the anticancer drug fulvestrant, were presented at the 2016 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) that is currently taking place in San Antonio, Texas (Press release, Puma Biotechnology, DEC 7, 2016, View Source [SID1234516992]). The presentation entitled "Neratinib plus fulvestrant for ERBB2 mutant, HER2 non-amplified, estrogen receptor-positive, metastatic breast cancer: Preliminary analysis from the Phase II SUMMIT trial" was presented as a poster discussion by Dr. David Hyman, Director, Developmental Therapeutics at Memorial Sloan Kettering Cancer Center.

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Interim results from this trial were previously presented at the 2015 SABCS and included patients who were treated with neratinib monotherapy for metastatic breast cancer and whose tumors have a HER2 mutation. The presentation also discussed that a bidirectional cross-talk between hormone receptor and HER2 signaling pathways could lead to endocrine resistance due to activated HER2 signaling and ER-mediated tumor proliferation as a potential resistance mechanism to sustained HER2 inhibition. Preclinical xenograft data has demonstrated that the combination of an anti-estrogen with neratinib results in enhanced anti-tumor activity in preclinical models of estrogen receptor positive/HER2-positive breast tumors. Based on this, the SUMMIT study was amended to allow for the combination of neratinib plus fulvestrant in eligible postmenopausal hormone receptor-positive breast cancer patients. The presentation at SABCS included an update on both the neratinib monotherapy cohort and the neratinib plus fulvestrant cohort.

In the study, patients with HER2 mutant metastatic breast cancer were enrolled and received 240 mg of neratinib daily either as monotherapy or in combination with fulvestrant. All patients received loperamide (16 mg per day initially) prophylactically for the first cycle of treatment in order to reduce the neratinib-related diarrhea. For the 25 patients in the group who received neratinib monotherapy, 23 patients (92%) had HER2-negative disease, 19 patients (76%) were hormone receptor positive (estrogen receptor or progesterone receptor positive), and patients had received a median of 4 prior lines of therapy in the metastatic setting (range 0-8 prior regimens) before entering the trial. For the 17 patients in the trial who received neratinib plus fulvestrant, 15 patients (88%) had HER2-negative disease, 17 patients (100%) were hormone receptor positive (estrogen receptor or progesterone receptor positive), and patients had received a median of 4 prior lines of therapy in the metastatic setting (range 1-7 prior regimens) before entering the trial.

The interim efficacy results from the trial showed that for the 24 efficacy evaluable patients in the neratinib monotherapy cohort, 8 patients (33.3%) experienced an objective response, which included 3 patients with a complete response and 5 patients with partial responses. At week 8, 8 patients (33.3%) achieved an objective response, with 2 patients achieving a complete response and 6 patients achieving a partial response The secondary endpoints of the trial included confirmed objective response (complete response or partial response), clinical benefit rate and progression free survival (PFS). The results of the trial showed that 6 patients (25%) had a confirmed objective response, 10 patients (41.7%) demonstrated clinical benefit and the median progression free survival was 3.5 months.

For the 12 efficacy evaluable patients in the neratinib plus fulvestrant cohort, 7 patients (58.3%) experienced an objective response, which included 2 patients with a complete response and 5 patients with partial responses. At week 8, 5 patients (41.7%) achieved an objective response, with 2 patients achieving a complete response and 3 patients achieving a partial response. The secondary endpoints of the trial included confirmed objective response (complete response or partial response), clinical benefit rate and progression free survival (PFS). The results of the trial showed that 3 patients (25%) had a confirmed objective response, 7 patients (58.3%) demonstrated clinical benefit and the median progression free survival was 3.7 months. The progression free survival data may not be mature in the neratinib plus fulvestrant cohort as 4 of the 12 efficacy evaluable patients are continuing to receive study treatment without disease progression and an additional 5 patients have not yet had an assessment for efficacy.

The interim safety results of the study showed that the most frequently observed adverse event was diarrhea. For the 25 patients enrolled in the neratinib monotherapy arm, 6 patients (24%) reported grade 3 diarrhea. The median duration of grade 3 diarrhea for the patients in the neratinib monotherapy cohort was 1 day. No patient in the neratinib monotherapy cohort has permanently discontinued neratinib due to diarrhea and 5 patients (20%) have temporarily discontinued neratinib due to diarrhea and then restarted after the diarrhea subsided. For the 17 patients enrolled in the neratinib plus fulvestrant cohort, 2 of 17 patients (12%) experienced grade 3 diarrhea. The median duration of grade 3 diarrhea was 1 day and typically occurred during the first cycle of treatment. No patient (0%) in the neratinib plus fulvestrant cohort permanently discontinued neratinib due to diarrhea and 2 patients (12%) temporarily discontinued neratinib due to diarrhea and then restarted after the diarrhea subsided.

Dr. David Hyman, Director, Developmental Therapeutics at Memorial Sloan Kettering Cancer Center and principal investigator of the trial, stated, "Neratinib showed promising signs of clinical activity both as a single agent and in the patients treated with the combination of neratinib plus fulvestrant in this preliminary analysis of pre-treated HER2 mutant breast cancer patients. The safety profile of the drug was manageable and the diarrhea was not treatment-limiting with appropriate prophylaxis and management. We look forward to completing the ongoing neratinib plus fulvestrant cohort and moving this combination forward into future clinical development."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are very pleased with the preliminary activity seen with neratinib, both alone and in combination with fulvestrant in this cohort of patients with HER2 mutated breast cancer. We look forward to the completion of the trial and further development of the combination of neratinib and fulvestrant."

On December 6, 2016 Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical stage biotechnology company focused on the development of novel cancer therapeutics, reported that clinical data from its lead product candidate CB-839, a first-in-class glutaminase inhibitor, will be presented at the 2016 San Antonio Breast Cancer Symposium, December 6-10, 2016 in San Antonio, Texas (Press release, Calithera Biosciences, DEC 6, 2016, View Source;p=RssLanding&cat=news&id=2227919 [SID1234516955]). The data demonstrate the clinical activity, tolerability and unique mechanism of action of CB-839 in patients with advanced/metastatic triple negative breast cancer (TNBC).

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"Triple negative breast cancer in the advanced and metastatic population remains a significant unmet need. We are particularly pleased to observe responses with CB-839 plus paclitaxel in taxane-refractory patients," said Susan Molineaux, PhD, President and Chief Executive Officer of Calithera.

Dr. Angela DeMichele from the University of Pennsylvania will present in a poster session, "Phase I study of CB-839, a small molecule inhibitor of glutaminase, in combination with paclitaxel in patients with triple negative breast cancer," (Abstract P6-11-05). The abstract was selected for presentation on Saturday, December 10, 2016. Eligible patients must have locally advanced/metastatic TNBC, with prior paclitaxel treatment allowed. As of November 25, 2016, 28 triple negative breast cancer patients had been treated with doses of CB-839 of 400, 600 or 800 mg bid in combination with 80 mg/m2 IV paclitaxel, weekly, three weeks out of four; 23 were evaluable for response. The majority of patients had received at least three prior lines of therapy, with 43% of patients treated with five or more prior therapies in the advanced/metastatic setting. Most patients had received prior taxane therapy in either the neo-adjuvant or metastatic setting. Among evaluable patients treated with CB-839 doses of at least 600 mg bid (n=16), there are 5 partial responses (31%) and disease control (response or stable disease) in 11 patients (69%). In addition, the combination overcomes resistance to paclitaxel in heavily pretreated TNBC patients. There is a 38% response rate and 50% disease control rate in patients who received prior taxanes in the metastatic setting. There is a 50% response rate among taxane-refractory African American patients, consistent with higher glutamine utilization observed in tumors from this population.1

The combination of CB-839 and paclitaxel has been well tolerated to date, with adverse events that have been easily manageable and reversible, including several paclitaxel related toxicities. There was one case of dose-limiting, recurrent grade 3 neutropenia at the 400 mg dose level, which led to a reduction in the dose of paclitaxel for that patient. The most frequent adverse event ≥ Grade 3 is neutropenia (n=6).

On December 6, 2016 TG Therapeutics, Inc. (NASDAQ:TGTX), reported the presentation yesterday of data from three combination studies involving the Company’s lead compounds, TGR-1202, the Company’s once-daily PI3K delta inhibitor, and TG-1101 (ublituximab), the Company’s novel glycoengineered anti-CD20 monoclonal antibody at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, in San Diego, California (Press release, TG Therapeutics, DEC 6, 2016, View Source [SID1234516973]).

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Michael S. Weiss, the Company’s Executive Chairman and Interim CEO stated, "We are very pleased to continue to see a highly differentiated safety profile for TGR-1202 across multiple double and triple combination studies with a high level of activity. Each of the four clinical studies presented at the ASH (Free ASH Whitepaper) meeting, enhanced our overall understanding of the breadth of activity of TGR-1202. In addition to DLBCL, FL and CLL, where we have already shown data previously, it was nice to see the flexibility of TGR-1202 and its ability to be combined with brentuximab vedotin in relapsed or refractory Hodgkin’s and with ruxolitinib in Myelofibrosis." Mr. Weiss continued, "We are also encouraged by the triple combination data of TG-1101, TGR-1202, and bendamustine in relapsed or refractory, difficult to treat, DLBCL and FL patients which showed no discontinuations for a treatment related adverse event, as well as an 80% overall response rate across both DLBCL and FL patients and a high level of CR’s. We, and our investigators, believe this triplet combination is a promising regimen and plan to study it in this patient population in a registration-directed trial."

Highlights from yesterday’s presentations include the following:

Poster Presentation: Combination of Ublituximab, TGR-1202, and Bendamustine Demonstrates Significant Activity in Patients with Advanced DLBCL and Follicular Lymphoma (Abstract Number 4197)

This poster presentation includes data from patients with relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL) or Follicular Lymphoma (FL) treated with the triple combination of TG-1101 (ublituximab), TGR-1202 and bendamustine. Nineteen patients were evaluable for safety of which 15 were evaluable for efficacy (3 patients were too early to evaluate and 1 patient had a non-related adverse event (AE) prior to efficacy assessment). The triple combination appears well tolerated with no discontinuations for a treatment related AE. Neutropenia and anemia were the only Grade 3/4 AE’s occurring in more than 1 patient. Importantly, no Grade 3/4 transaminitis was reported, no events of pneumonia or pneumonitis, and only 1 transient event of Grade 3 diarrhea, with a duration of 1 day, was observed. Eleven patients (58%) were refractory to prior treatment. Median time on study at the data cut off was approximately 6 months with the majority of patients continuing on study and follow-up ongoing.

Efficacy highlights from this poster include:

71% (5 of 7) Overall Response Rate (ORR), including a 43% Complete Response (CR) rate observed in patients with relapsed or refractory DLBCL
88% (7 of 8) ORR, including a 37% CR rate observed in patients with relapsed or refractory FL 4/6 CR’s that were achieved between the DLBCL and FL groups occurred at the first 8 week efficacy assessment
First response assessment occurred at Month 3 following initiation of therapy, with durable responses observed notably amongst DLBCL patients.
Poster Presentation: A Phase I Trial of TGR-1202, a Next Generation Once-Daily PI3Kδ Inhibitor, in Combination with Brentuximab Vedotin, in Patients with Relapsed/Refractory Hodgkins Lymphoma (Abstract Number 4146)

This poster presentation includes data from patients with relapsed and refractory Hodgkin’s Lymphoma (HL) treated with TGR-1202 at either 400mg or 600mg dosed orally once daily in combination with brentuximab vedotin in continuous 21 day cycles. 14 patients were evaluable for safety, of which 11 were evaluable for efficacy (3 discontinued prior to disease evaluation (2 AE’s and 1 withdrew consent)). 43% (6 of 14) of patients had prior exposure to brentuximab vedotin and all were refractory to prior brentuximab vedotin therapy. The combination demonstrated tolerability with nausea, diarrhea, and neutropenia being the most prevalent adverse events. Notably all but one case of diarrhea was Grade 1 or 2 in severity.

Efficacy highlights from this poster include:

60% (3 of 5) ORR, including a 40% CR rate observed across brentuximab vedotin refractory patients
64% (7 of 11) ORR, including a 45% CR rate observed across all patients treated

Oral Presentation: Preliminary Results from a Phase I Dose Escalation Trial of Ruxolitinib and the PI3Kδ Inhibitor TGR-1202 in Myelofibrosis (Abstract Number 1125)
This oral presentation includes data from patients with myelofibrosis treated with the combination of ruxolitinib, the JAK1/2 inhibitor and TGR-1202. The combination was well tolerated and efficacious in the twelve patients treated. The most prevalent adverse events deemed at least possibly related to TGR-1202 included anemia, thrombocytopenia, neutropenia, AST/ALT elevation and amylase/lipase elevation and diarrhea, all of which were notably Grade 1/2 with the exception of Grade 3 amylase/lipase elevation seen in 2 patients (16.7%), and Grade 3 diarrhea seen in 1 patient (8.3%). Presentation highlights included:

The patient population enrolled was advanced, with the majority having 2 or more prior mutations at baseline;
Per protocol, all enrolled patients were on a stable dose of ruxolitinib monotherapy with best response to ruxolitinib monotherapy achieved prior to enrollment;
Following the addition of TGR-1202, 11/12 patients experienced improvement in hemoglobin, many with a concomitant reduction in platelet counts indicating clinical benefit beyond ruxolitinib monotherapy; and
83% of study participants experienced clinical benefit (hematologic improvement, reduced spleen size and/or improvement in symptoms) including one patient who achieved a CR and continues on study, now out 72 weeks

PRESENTATION DETAILS:
Copies of the above referenced presentations are available on the Company’s website at www.tgtherapeutics.com, located on the Publications page.

TG THERAPEUTICS INVESTOR & ANALYST EVENT:
TG Therapeutics held an investor and analyst reception yesterday, at the Marriott Gaslamp, in San Diego, California. The audio file and slide presentation are available for review on the Events page, located within the Investors & Media section of the Company’s website at www.tgtherapeutics.com.

On December 6, 2016 Kite Pharma, Inc. (Nasdaq:KITE) reported results from the ZUMA-1 trial of axicabtagene ciloleucel (KTE-C19) in patients with chemorefractory aggressive non-Hodgkin lymphoma (NHL) in two oral presentations at the American Society of Hematology (ASH) (Free ASH Whitepaper) 58th Annual Meeting in San Diego, California (Press release, Kite Pharma, DEC 6, 2016, View Source [SID1234516957]).

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ZUMA-1 enrolled 111 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL). Patients were required to have chemorefractory disease, defined as progressive or stable disease as best response to last line of therapy, or disease progression ≤12 months after autologous stem cell transplant. Manufacturing was successful for 110 patients, and 101 patients were treated. The pre-specified interim analysis was triggered when 51 patients with DLBCL had a minimum of three months of follow-up. At the time of interim analysis, 11 patients with PMBCL/TFL had been followed for three months. An additional 31 patients with one month of follow-up were included in the late breaker presentation.

"The vast majority of patients enrolled in ZUMA-1 are unable to undergo autologous stem cell transplant due to chemorefractory disease. This group has a dire need for more effective therapies," said Jeff Wiezorek, M.D., Senior Vice President of Clinical Development. "We are encouraged by the high rate of complete remissions in this group and look forward to presenting longer follow-up at the primary analysis in the first quarter 2017. We are grateful to the patients and investigators who have made this important study possible."

ZUMA-1 met the primary endpoint of objective response rate (ORR), p < 0.0001. Response rates by disease subtype are shown in the table below. Responses were observed across key subgroups, including 75 percent CR in patients who relapsed in ≤12 months after autologous stem cell transplant and 47 percent CR in patients refractory to second line or later chemotherapy. At the month three assessment, 39 percent of patients were in CR.

Best Overall Response in Patients with ≥3 Month Follow-up
Subgroup
N ORR CR
DLBCL
51 76% 47%
TFL / PMBCL 11 91% 73%
Total 62 79% 52%
In 93 patients with a minimum one month follow-up, the most common grade 3 or higher adverse events included neutropenia (63 percent), anemia (42 percent), leukopenia (40 percent), febrile neutropenia (29 percent), thrombocytopenia (26 percent), encephalopathy (19 percent), hypophosphatemia (17 percent), and decreased lymphocyte count (17 percent). Grade 3 or higher CRS and NE were observed in 13 percent and 29 percent of patients, respectively. Three patients died from treatment-emergent adverse events (hemophagocytic lymphohistiocytosis, cardiac arrest in the setting of CRS and pulmonary embolism). There were no cases of cerebral edema.

The primary analysis of ZUMA-1 will include a minimum of 6 months of follow-up. Kite intends to seek regulatory approval of axicabtagene ciloleucel in refractory aggressive NHL and plans to complete its rolling submission of the Biologics License Application (BLA) in the first quarter of 2017.

The late-breaker abstract (LBA-6), "KTE-C19 (anti-CD19 CAR T Cells) Induces Complete Remissions in Patients with Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Results from the Pivotal Phase 2 ZUMA-1," was presented by Sattva S. Neelapu, M.D., Associate Professor, Deputy Department Chair ad interim, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. View Source

About axicabtagene ciloleucel

Kite Pharma’s lead product candidate, axicabtagene ciloleucel, is an investigational therapy in which a patient’s T cells are engineered to express a chimeric antigen receptor (CAR) to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias, and redirect the T cells to kill cancer cells. Axicabtagene ciloleucel has been granted Breakthrough Therapy Designation status for diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL) by the U.S. Food and Drug Administration (FDA) and Priority Medicines (PRIME) regulatory support for DLBCL in the EU.

On December 6, 2016 TG Therapeutics, Inc. (NASDAQ:TGTX), reported that the target enrollment of 120 patients in the GENUINE Phase 3 study has been met and enrollment will be closed shortly (Press release, TG Therapeutics, DEC 6, 2016, View Source [SID1234516974]). The GENUINE Phase 3 study is a randomized study of TG-1101, the Company’s novel, glycoengineered anti-CD20 monoclonal antibody in combination with ibrutinib, the oral Bruton’s tyrosine kinase (BTK), versus ibrutinib alone in approximately 120 patients with high-risk relapsed or refractory Chronic Lymphocytic Leukemia (CLL). In October, the study was modified to convert the primary endpoint solely to Overall Response Rate (ORR). If the study results are positive, and subject to a positive outcome of pre-BLA meeting with the FDA, the Company plans to utilize the results to file for accelerated approval. The Company expects to release top-line data from the GENUINE Phase 3 study in the first half of 2017.

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Michael S. Weiss, the Company’s Executive Chairman and Interim CEO commenting on the announcement stated, "Today’s news puts us on a clear path toward our first pivotal data for TG-1101. As demonstrated in our Phase 2 study evaluating TG-1101 plus ibrutinib, we believe the addition of an anti-CD20 monoclonal antibody can enhance the clinical response of single agent ibrutinib by more rapidly reducing tumor burden, increasing the rate of response, deepening responses and, ideally, leading to better long-term outcomes. Overall response rate has been utilized as an acceptable surrogate endpoint for improved progression free survival and overall survival for a number of recent approvals in high-risk CLL and we believe the results, if positive, may support an accelerated approvable for the combination. We want to thank our clinical collaborators and their patients for their participation in this study."