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Puma Biotechnology Presents Interim Results of Phase II CONTROL Trial of PB272 in Extended Adjuvant Treatment of HER2-Positive Early Stage Breast Cancer at the 2017 AACR Annual Meeting

On April 4, 2017 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that interim results from a Phase II clinical trial of Puma’s investigational drug PB272 (neratinib) were presented at the 2017 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (AACR) (Free AACR Whitepaper) that is currently taking place in Washington, D.C (Press release, Puma Biotechnology, APR 4, 2017, View Source [SID1234518463]). The presentation, entitled "Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2-positive early stage breast cancer: the CONTROL trial," was presented as a poster presentation.

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The main adverse event that has been seen to date in clinical trials of neratinib is diarrhea and more specifically grade 3 diarrhea. In the Phase III ExteNET trial of neratinib as extended adjuvant treatment of HER2-positive early stage breast cancer that has previously been treated with adjuvant Herceptin, 95.4% of the patients experienced all grade diarrhea and 39.8% of the patients experienced grade 3 or higher diarrhea (there was one event of grade 4 diarrhea). The CONTROL trial is an international, open-label, Phase II study investigating the use of loperamide prophylaxis with or without other agents in the reduction of neratinib-associated diarrhea that has a primary endpoint of the incidence of grade 3 diarrhea.

In the CONTROL trial, patients with HER2-positive early stage breast cancer who had completed trastuzumab-based adjuvant therapy received neratinib daily for a period of one year. High dose loperamide prophylaxis was given for the first 2 cycles (56 days) of treatment. Initially, the loperamide dosing used was 16 mg on day 1, then 12 mg on days 2 and 3 and then 6-8 mg on days 4-56 (original dosing). The protocol was later amended to simplify the regimen such that patients took 12 mg on days 1-14 and 8 mg on days 15-56 (modified dosing). The CONTROL trial was also expanded to include two additional cohorts. One cohort received the combination of loperamide and budesonide and the other cohort received the combination of loperamide plus colestipol. Budesonide is a locally acting corticosteroid that the Company believes targets the inflammation identified in a preclinical model of neratinib-induced diarrhea and colestipol is a bile acid sequestrant that the Company believes targets the bile acid malabsorption also seen in preclinical models of neratinib-induced diarrhea.

The interim analysis of the trial presented in the poster included a total of 137 patients who received neratinib plus loperamide prophylaxis (28 patients taking the original dosing and 109 patients taking the modified dosing), 64 patients who received neratinib plus loperamide prophylaxis for 2 cycles and budesonide for 1 cycle, and 26 patients who received neratinib plus loperamide prophylaxis for 1 cycle and colestipol for 1 cycle.

The results of the trial showed that the incidence of grade 3 diarrhea for the 137 patients who received the loperamide prophylaxis was 30.7%. For the 137 patients who received the loperamide prophylaxis, the median number of grade 3 diarrhea episodes per patient was 1 and the median cumulative duration of grade 3 diarrhea was 3 days. For the 137 patients who received loperamide prophylaxis, 20.4% discontinued neratinib due to diarrhea.

For the 64 patients who received the combination of loperamide plus budesonide, the results of the trial showed that the incidence of grade 3 diarrhea was 23.4%. The median number of grade 3 diarrhea episodes per patient was 1 and the median cumulative duration of grade 3 diarrhea was 2 days. For the 64 patients who received loperamide plus budesonide prophylaxis, 9.4% discontinued neratinib due to diarrhea.

For the 26 patients who received the combination of loperamide plus colestipol, the results of the trial showed that the incidence of grade 3 diarrhea was 11.5%. The median number of grade 3 diarrhea episodes per patient was 2 and the median cumulative duration of grade 3 diarrhea was 2 days. For the 26 patients who received loperamide plus colestipol prophylaxis, no patient (0%) discontinued neratinib due to diarrhea. Further information is provided in Table 1 below:

Table 1: Characteristics of Treatment-Emergent Diarrhea

Study CONTROL ExteNET
Antidiarrheal prophylaxis
Loperamide
Budesonide Colestipol

(original +
modified)
+
loperamide
+
loperamide

Loperamide
prn
N (at data cut-off) 137 64 26 1408
Diarrhea, %
Any grade 77.4 79.7 57.7 95.4
Grade 1 24.1 26.6 30.8 22.9
Grade 2 22.6 29.7 15.4 32.5
Grade 3 30.7 23.4 11.5 39.8
Grade 4 0 0 0 0.1

Median cumulative duration of diarrhea, days
Any grade 12.0 10.0 8.0 59.0
Grade ≥2 4.0 3.0 2.0 10.0
Grade ≥3a 3.0 2.0 2.0 5.0

Median episodes of diarrhea per patient, n
Any grade 2.0 4.0 3.0 8.0
Grade ≥2 2.0 2.0 2.0 3.0
Grade ≥3a 1.0 1.0 2.0 2.0

Median duration of neratinib treatment, months
Median 10.6 5.1 1.7 11.6

Tolerability related to neratinib diarrhea
Neratinib dose hold due to diarrhea, % 14.6 14.1 7.7 33.9
Neratinib dose reductions due to diarrhea, % 7. 3 1.6 3.8 26.4
Neratinib discontinuations due to diarrhea, % 20.4 9.4 0 16.8
Hospitalization due to diarrhea, % 1. 5 0 0 1.4
a
No grade 4 events in the CONTROL study; one grade 4 event in the ExteNET study.

In the ExteNET trial, higher grade (grade 2 and grade 3) diarrhea occurred early and persisted throughout the duration of the 12-month treatment period. In the CONTROL trial, in the loperamide prophylaxis, loperamide plus budesonide prophylaxis and loperamide plus colestipol prophylaxis arms, the results showed that higher grade diarrhea (grades 2 and 3) occurred early but did not typically recur. This is shown in more detail in Figure 1: Treatment Emergent Diarrhea, which is attached to this news release. In addition, a full copy of the poster that was presented at AACR (Free AACR Whitepaper) is available on the Puma Biotechnology website.

During the course of the CONTROL trial there has been an increase in the proportion of patients previously treated with pertuzumab (mainly in the neoadjuvant setting). For the 55 patients in the loperamide prophylaxis cohort who received prior pertuzumab, the grade 3 diarrhea rate was 38.2% (Table 2). For the 82 patients who did not receive prior pertuzumab, the grade 3 diarrhea rate was 25.6%. For the 39 patients in the budesonide cohort who received prior pertuzumab, the grade 3 diarrhea rate was 10.3%. For the 25 patients in the budesonide cohort who did not receive prior pertuzumab, the grade 3 diarrhea rate was 36.0%. This analysis suggests that prior pertuzumab exposure may have led to a higher rate of grade 3 diarrhea in the CONTROL trial that was not effectively managed by loperamide prophylaxis alone but was more effectively managed by loperamide plus budesonide.

Table 2: Incidence of Grade 3 Diarrhea in CONTROL by Prior Pertuzumab Treatment

Loperamide Cohort

Budesonide Cohort

Yes No Yes No
(n = 55)
(n = 82)
(n = 39)
(n = 25)

Grade 3 Diarrhea 38.2% 25.6% 10.3% 36.0%

Dr. Carlos H. Barcenas, Assistant Professor, Department of Breast Medical Oncology and Associate Medical Director, Breast Cancer Survivorship Clinic for the University of Texas MD Anderson Cancer Center, said, "We are pleased to see the reduction in incidence, severity and duration of neratinib-associated diarrhea when using the three antidiarrheal prophylaxis regimens tested so far in this study. When using either the loperamide prophylaxis, the loperamide plus budesonide prophylaxis or the loperamide plus colestipol prophylaxis, there appears to be a reduction in the incidence and severity of grade 3 diarrhea with neratinib. Importantly, the severe grade 2 and grade 3 diarrhea, when using the prophylaxis, appears to be acute, self-limiting and manageable. Although the study is still ongoing, we are encouraged that the addition of budesonide or colestipol appears to greatly improve the tolerability of neratinib as well. We look forward to completing the loperamide plus colestipol cohort."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are pleased to see the reductions in the incidence of severe neratinib-related diarrhea in the CONTROL trial when using the loperamide, loperamide plus budesonide or loperamide plus colestipol regimens. The severe diarrhea appears to become more acute, whereby it does not typically recur after the first month. We are also very encouraged by the improvements in tolerability that have been seen to date in the budesonide and the colestipol cohorts. This is a marked improvement in tolerability over what was seen in the ExteNET trial and we look forward to continuing to monitor this in the loperamide plus colestipol cohort."

Onconova Therapeutics Announces Positive Preclinical Data for Third-Generation Oral CDK4/6 + ARK5 Inhibitor and dual FLT3 and Src inhibitor at 2017 American Association of Cancer Research (AACR) Annual Meeting

On April 4, 2017 Onconova Therapeutics, Inc. (Nasdaq: ONTX), a Phase 3 stage biopharmaceutical company focused on discovering and developing small molecule drug candidates to treat cancer, with a primary focus on Myelodysplastic Syndromes, reported promising pre-clinical data for first-in-class dual inhibitor of CDK4/6 + ARK5, as well as a Type 1 novel inhibitor of FLT3 and Src pathways as a novel strategy for Acute Myeloid Leukemia (AML) therapy at the 2017 AACR (Free AACR Whitepaper) Annual Meeting (Press release, Onconova, APR 4, 2017, View Source [SID1234518461]). The Company presented its findings in two poster presentations on April 3, 2017.

ON 123300, an orally administered novel CDK4/6 + ARK5 inhibitor, exhibits potent antitumor activity in vivo: comparative studies with Palbociclib

ON 123300, a third-generation potent CDK4/6 inhibitor that also inhibits ARK5 with low nanomolar potency, was found to be as effective as Palbociclib (Pfizer’s Ibrance) in an Rb + ve xenograft model. Moreover, the molecule may have the potential advantage of reduced neutropenia when compared to Palbociclib. Both compounds decreased RBC and platelet counts, however in this model system, Palbociclib had a more prominent and statistically significant (P≤0.05) inhibitory effect on neutrophil counts when compared to ON 123300 (30.70 ± 3.55 vs. 45.10 ± 2.04).

"There is a need for next-generation CDK4/6 inhibitors such as ON 123300, given the limitations of second-generation compounds that depend on a second molecule for therapeutic use. We are particularly excited about ON 123300 because of its potential to act as a single agent, as a dual inhibitor of CDK 4/6 + ARK 5 and which could be suitable for indications that may not be amenable to Palbociclib-like compounds," said Dr. Ramesh Kumar, CEO of Onconova.

A full copy of the above AACR (Free AACR Whitepaper) poster can be accessed by visiting "Scientific Presentations" in the Investors and Media section of Onconova’s website.

Dual inhibition of FLT3 and Src pathways by ON 150030, a type 1 inhibitor, as a novel strategy for relapsed and refractory AML

Biological studies at the Icahn School of Mount Sinai reveal that ON 150030 specifically inhibits the growth of MV4-11 cells harboring the FLT3-ITD mutation (GI50: 10nM). Western blot analysis demonstrates that MAPK and PI3K/AKT pathways in these cells are inhibited with increasing dose of ON 150030. The JAK independent phosphorylation of STAT5 seen in the context of FLT3-ITD is also reduced in response to ON 150030. The poor survival rate among FLT3-ITD positive AML patients and the resistance associated with current treatment regimens highlight a need for a novel FLT3 inhibitor that will be effective in cells resistant to Quizartinib.

"We are excited by the positive data on these two preclinical compounds, which address dual targeting strategy to address difficult to treat diseases. These promising results underscore the depth of our clinical pipeline, which is led by rigosertib, an advanced Phase 3 stage innovation for the treatment of patients with myelodysplastic syndromes. Following the advancement of our late stage trials in 2016, rigosertib is positioned for multiple key milestones in 2017," concluded Dr. Kumar.

Interim Phase 2 Data Demonstrate Robust Response Rate with Indoximod in Combination with Keytruda® (pembrolizumab) for Patients with Advanced Melanoma at AACR Plenary

On April 4, 2017 NewLink Genetics Corporation (NASDAQ:NLNK), a biopharmaceutical company focused on bringing novel immuno-oncology therapies to patients with cancer, reported interim results from NLG2103, a Phase 2 study evaluating its IDO pathway inhibitor, indoximod, in combination with checkpoint inhibitors for the treatment of patients with advanced melanoma (Press release, NewLink Genetics, APR 4, 2017, View Source [SID1234518460]).

An infographic accompanying this release is available at
View Source

These data report on a cohort of 60 evaluable patients (including patients with ocular melanoma) who received the combination of indoximod plus pembrolizumab which demonstrated a 52% (31/60) ORR and a 73% (44/60) DCR. Patients with non-ocular melanoma achieved a 59% (30/51) ORR and an 80% (41/51) DCR. The combination was generally well tolerated with low rates of Grade 3 or higher adverse events. These data will be presented today in the Clinical Trials Plenary Session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2017 Annual Meeting in Washington, D.C.

"These data are impressive and demonstrate the potential of this combination to improve response rates of the currently available therapy for patients with advanced melanoma. Importantly, our combination therapy was well tolerated without an appreciable increase in toxicity," said Dr. Yousef Zakharia, M.D., Assistant Professor of Medicine, Division of Hematology, Oncology and Blood & Marrow Transplantation at the University of Iowa and Holden Comprehensive Cancer Center, a leading investigator on the trial.

Nicholas Vahanian, M.D., President and Chief Medical Officer said, "These new data further underscore the potential for indoximod in combination with other agents. The ORR and DCR are highly encouraging and further validate indoximod as a promising IDO pathway inhibitor."

Charles J. Link, Jr., M.D., Chairman and Chief Executive Officer said, "Currently approved immunotherapies are transforming cancer treatment. We believe targeting the IDO pathway is key to enhancing the efficacy of existing and future treatment regimens. NewLink Genetics has two distinct IDO pathway inhibitors in development that represent separate and independent opportunities. We expect further clinical validation of the IDO pathway as an immuno-oncology target throughout 2017."

NLG2103 is a Phase 2 study evaluating the addition of indoximod to the standard of care checkpoint inhibitors approved for patients with advanced melanoma (pembrolizumab, ipilimumab, or nivolumab). The interim data represent a cohort of 60 evaluable patients who received indoximod plus pembrolizumab. Evaluable patients were defined as those having at least one on-treatment imaging study. The primary outcome measure of the trial is objective response rate (ORR) and secondary outcome measures include disease control rate (DCR) and evaluation of safety and tolerability.

Key findings:

The ORR, by site reported RECIST criteria, for all patients was 52% (31/60) with a 73% (44/60) DCR.
Patients with non-ocular melanoma achieved a 59% (30/51) ORR and a DCR of 80% (41/51).
The majority of responses reported have been durable.
The occurrence of Grade 3 or greater adverse events was low with no apparent increase for the combination over what would be expected with pembrolizumab alone.
About Indoximod
Indoximod is an investigational, orally available small molecule targeting the IDO Pathway. The IDO Pathway is one of the key immuno-oncology targets involved in regulating the tumor microenvironment and immune escape.

NewLink Genetics is currently evaluating indoximod in multiple combination studies for patients with various types of cancer. These include melanoma, acute myeloid leukemia, pancreatic cancer and prostate cancer.

Nektar Therapeutics Presents New Preclinical Data for its Immuno-Oncology Programs at the American Association for Cancer Research (AACR) Annual Meeting

On April 4, 2017 Nektar Therapeutics (Nasdaq: NKTR) reported five preclinical data presentations for its immuno-oncology programs made at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2017 (Press release, Nektar Therapeutics, APR 4, 2017, View Source [SID1234518459]). The presentations featured new preclinical data on NKTR-214, the Company’s immuno-stimulatory CD122-biased agonist, as well as on NKTR-255, the Company’s IL-15 therapeutic candidate.

Stephen Doberstein, Ph.D., Nektar’s Senior Vice President and Chief Scientific Officer commented, "The preclinical studies presented at AACR (Free AACR Whitepaper) by both Nektar scientists and our academic collaborators highlight the unique mechanistic profiles of Nektar’s two novel cytokine therapies, NKTR-214 and NKTR-255, including their ability to stimulate multiple cancer-killing CD8+ T cell subtypes within the tumor micro-environment. These data showcase how Nektar’s technology can be leveraged to target the IL-2 and IL-15 pathways in new ways in order to stimulate the body’s immune system to fight cancer."

NKTR-214 is a CD122-biased agonist designed to grow specific cancer-killing T cells and natural killer (NK) cell populations in the body which fight cancer, which are known as endogenous tumor-infiltrating lymphocytes (TILs). NKTR-214 stimulates these cancer-killing immune cells in the body by targeting CD122 specific receptors found on the surface of these cancer-killing immune cells, known as CD8+ effector T cells and Natural Killer (NK) cells. NKTR-214 is currently in Phase 1/2 clinical development.

NKTR-255 is a memory T cell stimulating cytokine designed to engage the IL-15 pathway to induce long-term T cell activation and improve the quality of T cell memory response to treat cancer. Through optimal engagement of the IL-15Rα/IL-2Rγ receptor complex, NKTR-255 stimulates proliferation and survival of CD8+ T cells, natural killer (NK) cells and enhances formation of long-term immunological memory which may lead to sustained anti-tumor immune response.

Details of the five preclinical presentations made at AACR (Free AACR Whitepaper) are as follows:

Presenter: Seema Nagpal, M.D., Stanford University, Department of Neurology
Abstract 1598/Poster 6: "Single agent NKTR-214, an engineered IL2 pathway agonist, localizes in tumor tissue, increases immune infiltrates and prolongs survival in rodent (rattus) glioblastoma (GBM)"
Session: Cytokines: The First Modern Immunotherapies

NKTR-214 single agent provides durable responses as a single agent in an aggressive orthotopic rat brain tumor model.
Treatment of even very large tumors is effective with NKTR-214, prolonging survival in a significant proportion of animals; CD8+ T cells infiltrate into the brain tumors after NKTR-214 therapy.
The marked increase in survival in this aggressive rodent brain tumor model after treatment with single agent NKTR-214 suggests its potential benefit for the treatment of human malignant glioma.
Presenter: Michael J. McNamara, Ph.D., Earle A. Chiles Research Institute, Providence Portland Medical Center
Abstract 1604/Poster 12: "NKTR-214 Synergizes with Radiotherapy to Drive Tumor Regression"
Session: Cytokines: The First Modern Immunotherapies

NKTR-214 combines positively with radiation therapy which is a standard of care for multiple tumor types and is a readily available therapy.
Gene expression patterns reveal a strong T cell activation signature including up-regulation of tumor-killing granzymes and perforins.
Combined therapy increased the frequency of tumor-reactive CD8 T cells in the target (irradiated) tumors as measured by increased TCR ligation (Nur77-GFP+) and AH1-A5 tetramer staining.
Presenter: Giulia Parisi, Ph.D., Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles (UCLA)
Abstract 2671/Poster 30: "Antitumor activity of NKTR-214 in combination with Adopted Cell Transfer (ACT) in an aggressive murine melanoma"
Session: Immune Response to Hematopoietic Tumors: New Development in Tumor Immunology

NKTR-214 improves the antitumor activity of adoptive cellular therapy in an aggressive murine melanoma model.
Treatment with NKTR-214 + ACT robustly mobilizes T cells into the tumor where they durably persist.
The robust and long-lasting effect of NKTR-214 supports its potential use in combination with cell-based therapeutics.
Presenter: Samira Khalili, Ph.D., Nektar Therapeutics
Abstract 1617/Poster 25: "Mechanistic modeling of the pharmacokinetics, pharmacodynamics and receptor pharmacology of NKTR-214: A kinetically-controlled CD122 agonist for cancer immunotherapy"
Session: Cytokines: The First Modern Immunotherapies

NKTR-214 significantly favors occupancy at IL-2 receptor βγ compared to the IL-2 receptor αβγ.
NKTR-214 delivers a controlled, sustained, and biased signal through the IL-2 receptor complex.
Presenter: Peiwen Kuo, Ph.D., Nektar Therapeutics
Abstract 1603/Poster 11: "NKTR-255 engages the IL-15 pathway driving CD8 T cell survival and CD8 memory T cell proliferation"
Session: Cytokines: The First Modern Immunotherapies

NKTR-255 induces multiple memory CD8+ T cell subtypes, including effector, central and stem memory populations.
Single dose NKTR-255 results in sustained IL-15-mediated activity not achievable with conventional IL-15.
NKTR-255 has single agent efficacy in the CT-26 lung metastatic model, demonstrating significant lung nodule inhibition.

Kite Presents Promising Preclinical Data from KITE-585, a Fully Human Anti-BCMA CAR T-Cell Product Candidate at the 2017 American Association of Cancer Research (AACR) Annual Meeting

On April 4, 2017 Kite Pharma, Inc. (Nasdaq:KITE) reported new data presentations from preclinical studies related to KITE-585, a fully human anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell product candidate for the treatment of multiple myeloma (MM) at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Washington D.C (Press release, Kite Pharma, APR 4, 2017, View Source [SID1234518458]).

In today’s oral presentation (Abstract #4979), "Development of KITE-585: A fully human anti-BCMA CAR T-cell therapy for the treatment of multiple myeloma," KITE-585 demonstrated potent in vitro and in vivo activity against MM cell lines. CAR T cells were active in the presence of soluble BCMA and also eradicated established MM tumors in mice. KITE-585 contains a proprietary linker with the CD28 costimulatory domain. This configuration resulted in polyfunctional activation and proliferation of T-cells in the presence of MM cell lines, with no evidence of tonic signaling in the absence of target cells.

In the poster presentation (Abstract #2135), "Selectivity and specificity of engineered T cells expressing KITE-585, a chimeric antigen receptor targeting B-cell maturation antigen (BCMA)," the selectivity of KITE-585’s novel single-chain variable fragment (scFv) for BCMA was assessed using Retrogenix cell microarray technology. The results demonstrated the specificity of KITE-585 for BCMA expressing target cells.

"These promising preclinical data presented at AACR (Free AACR Whitepaper) suggest the potential of KITE-585 to offer a one-time treatment to address the high unmet need in multiple myeloma, an incurable blood cancer," said David Chang, M.D., Ph.D., Executive Vice President, Research and Development, and Chief Medical Officer. "The roadmap developed for the clinical development and manufacturing expertise of axicabtagene ciloleucel will be invaluable as we accelerate KITE-585 into the clinic later this year."

About Multiple Myeloma

Multiple myeloma (MM) is a rare and aggressive cancer. In 2016, there were an estimated 30,330 new cases of MM and 12,650 disease-related deaths in the U.S. alone.1 Nearly 95,000 people are either living with, or in remission from, MM.2 Treatment is chronic for most patients, usually with multi-therapy combinations, and most patients will eventually relapse.3 The median overall survival for high risk disease is 24-36 months.4

About KITE-585

KITE-585 is an investigational therapy in which a patient’s T cells are engineered to express a chimeric antigen receptor (CAR) to target the B cell maturation antigen (BCMA), a protein expressed on the cell surface of multiple myelomas (MM), and redirect the T cells to kill cancer cells. Kite expects to file an investigational new drug application (IND) for KITE-585 and initiate a Phase 1 clinical trial of KITE-585 in 2017.