1stOncology™: Cancer Intelligence Service – Page 15725 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

PharmaCyte Biotech Uses "Artificial Liver" to Treat Advanced Pancreatic Cancer

On July 7, 2016 PharmaCyte Biotech, Inc. (OTCQB: PMCB) reported that its signature live-cell encapsulation technology, Cell-in-a-Box, is being used in treatments for both cancer and diabetes (Press release, PharmaCyte Biotech, JUL 7, 2016, View Source [SID:1234513760]). For diabetes, the company’s therapy, which is made up of pinhead-sized, porous capsules filled with insulin producing cells, will create an "artificial pancreas" for type 1 diabetics and insulin-dependent type 2 diabetics that no longer produce their own insulin. Meanwhile, for cancer, the company’s therapy is made up of those same pinhead-sized, porous capsules; however, for advanced pancreatic cancer, they’re filled with genetically modified cells that act as a type of "artificial liver."

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!

First things first, PharmaCyte’s Cell-in-a-Box is not a drug delivery system. There are no drugs encapsulated inside the porous capsules for any of its treatments. Instead, for pancreatic cancer, which we will focus on today, the capsules are filled with about 10,000 live cells that are capable of converting an inactive chemotherapy drug (ifosfamide) into its active cancer-killing form — just as the enzyme system in a patient’s liver would normally do.

Keep in mind that because the chemotherapy drug ifosfamide is a prodrug or an inactive drug, it can travel all over the body and have no effect whatsoever until it is activated in the liver. Knowing that, PharmaCyte is, in a way, moving the "normal" conversion site (the patient’s liver) of that inactive drug closer to the cancerous tumor by using Cell-in-a-Box capsules and the live cells inside them to do the job of the patient’s liver or to act as an "artificial liver."

So how does the treatment work and why is it important to move the conversion site closer to the pancreatic tumor?

First, we will tackle how PharmaCyte’s therapy works.

The encapsulated live cells (Cell-in-a-Box capsules) are placed as close to the patient’s cancerous tumor as possible. Once implanted, ifosfamide, the aforementioned chemotherapy drug that needs to be activated in the body, is given to the patient intravenously at one-third the normal dose. The ifosfamide is then carried by the circulatory system to where the encapsulated cells have been placed. When the ifosfamide, which is normally activated in the liver, comes in contact with the encapsulated live cells in the Cell-in-a-Box capsules, the chemotherapy drug is activated into its cancer-killing form right at the site of the cancer.

This is "targeted chemotherapy" in the truest sense, and the company’s therapy has proven effective and safe to use in past clinical trials. This is how PharmaCyte will use its therapy in an upcoming Phase 2b clinical trial, so now let’s discuss why it’s important to move the drug activation site closer to the pancreatic tumor in the first place.

There are actually a number of reasons to move the activation site closer to the tumor. We’ll start with the chemotherapy drug itself. Ifosfamide, when activated, has a very short half-life (time before it decays and no longer offers any effect), so by using the cells inside the Cell-in-a-Box capsules to activate the drug at the site of the tumor, ifosfamide can immediately be the most effective when it’s the most potent before dying off minutes later.

Without a treatment like PharmaCyte’s, ifosfamide would be given to the patient intravenously and then activated "normally" in the liver, the activated drug would then affect tissues and organs other than the pancreas, and by the time it reached the pancreas, it undoubtedly would have lost much of its effectiveness. So, this, of course, means to be effective against a pancreatic tumor when the Cell-in-a-Box capsules are not used, a large dose of the drug has to be administered.

Using ifosfamide in such large doses has proven to be damaging for tissues and organs including the patient’s liver, and because the activated drug would come in contact with such other organs and good cells throughout the body on its way to the pancreas, the side effects would be intolerable; in fact, this is known to be the case.

By moving the conversion site as close to the tumor as possible, PharmaCyte is able to give a much smaller dose of the chemotherapy drug (one-third the normal dose), which patients are able to tolerate, and because of the smaller dose, the treatment can be administered without any side effects from the chemotherapy.

That’s right — chemotherapy without any side effects!

Heat Biologics Announces “Cancer Immunology Research” Publication Featuring its ComPACT Platform Technology

On July 07, 2016 Heat Biologics, Inc. (Nasdaq:HTBX), an immuno-oncology company developing novel therapies that activate a patient’s immune system against cancer, reported that a preclinical study on its next generation ComPACT platform technology, which combines a T cell priming vaccine and T cell co-stimulator in a single product, was published online in the journal "Cancer Immunology Research (Press release, Heat Biologics, JUL 7, 2016, View Source [SID:1234513758])." In the manuscript titled "Gp96-Ig/costimulator (OX40L, ICOSL or 4-1BBL) combination vaccine improves T-cell priming and enhances immunity, memory and tumor elimination," Heat demonstrated that its ComPACT technology secreting the co-stimulator OX40L significantly enhanced tumor rejection in two cancer tumor types (melanoma and colorectal cancer) compared to OX40 agonist antibody treatment. Heat also reported that ComPACT enhanced antigen-specific T cell infiltration into tumors, improved memory T cell responses and demonstrated greater specificity than OX40 agonist antibody treatments. In addition, the findings also showed that the ComPACT platform can be adapted to secrete other costimulatory molecules, including TL1A, 4-1BBL and ICOSL.

"We are pleased to have our work published in ‘Cancer Immunology Research.’ These data suggest that local vaccine co-stimulation has compelling advantages compared to systemic antibody co-stimulation," said Taylor Schreiber, M.D., Ph.D., Heat’s Chief Scientific Officer. "This combination platform provides flexibility to deliver multiple costimulatory ligands, which appear to outperform agonist antibodies in terms of immune response and tumor rejection, warranting further study in human clinical trials."

Kite Pharma Completes Enrollment of All Patients with Diffuse Large B-Cell Lymphoma (DLBCL) in Pivotal Multi-Center Phase 2 Study of KTE-C19 (ZUMA-1)

On July 7, 2016 Kite Pharma, Inc. (Nasdaq: KITE), a clinical-stage biopharmaceutical company focused on developing engineered autologous cell therapy (eACT) products for the treatment of cancer, reported that it has completed enrollment of 72 patients in DLBCL cohort in the Phase 2 portion of ZUMA-1 (Press release, Kite Pharma, JUL 7, 2016, View Source [SID:1234513763]). KTE-C19 is an investigational therapy in which a patient’s T-cells are genetically modified to express a chimeric antigen receptor (CAR) that is designed to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.

The DLBCL cohort of ZUMA-1 enrolled patients whose disease is chemorefractory (no response to last line of therapy or has relapsed within 12 month of autologous stem cell therapy). Patients received a lymphodepletion regimen that consisted of "low-dose" chemotherapy regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) daily for 3 days prior to infusion of the target KTE-C19 dose of 2 x 106 cells/kg.

"We are excited to complete enrollment in our first multi-center KTE-C19 study, an important milestone toward bringing this potential breakthrough therapy to patients with an urgent need for better treatment," said David Chang, M.D., Ph.D., Kite’s Executive Vice President, Research and Development, and Chief Medical Officer. "We are grateful to the patients and investigators who participated in our study. We look forward to announcing top-line data from the first 50 DLBCL patients in the ZUMA-1 study, and, subject to these results, plan on submitting our Biologics License Application (BLA) with the U.S. Food and Drug Administration by the end of 2016."

About Kite’s ZUMA Clinical Programs for KTE-C19

KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a CAR that is designed to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.

Study Phase Indication Status
ZUMA-1
NCT02348216 Phase 2 Pivotal
(N=112)
Chemorefractory DLBCL (N=72)
PMBCL, TFL (N=40)
Phase 2 enrollment complete
Phase 2 enrolling
ZUMA-2
NCT02601313 Phase 2 Pivotal
(N=70) Relapsed/refractory MCL Phase 2 enrolling
ZUMA-3
NCT02614066 Phase 1/2 Pivotal
(N=75) Relapsed/refractory Adult ALL Phase 1/2 enrolling
ZUMA-4
NCT02625480
Phase 1/2 Pivotal
(N=75) Relapsed/refractory Pediatric ALL Phase 1/2 enrolling

DLBCL = diffuse large B-cell lymphoma
PMBCL = primary mediastinal B-cell lymphoma
TFL = transformed follicular lymphoma
MCL = mantle cell lymphoma
ALL = acute lymphoblastic leukemia

Juno Therapeutics Reports Clinical Hold on the JCAR015 Phase II ROCKET Trial

On July 7, 2016 Juno Therapeutics, Inc. (NASDAQ:JUNO), a biopharmaceutical company focused on re-engaging the body’s immune system to revolutionize the treatment of cancer, reported that it has received notice from the U.S. Food and Drug Administration (FDA) that a clinical hold has been placed on the Phase II clinical trial of JCAR015 in adult patients with relapsed or refractory B cell acute lymphoblastic leukemia (r/r ALL), known as the "ROCKET" trial (Press release, Juno, JUL 7, 2016, View Source [SID:1234513762]). The clinical hold was initiated after two patient deaths last week, which followed the recent addition of fludarabine to the pre-conditioning regimen.

Juno has proposed to the FDA to continue the ROCKET trial using JCAR015 with cyclophosphamide pre-conditioning alone. In response, the FDA has requested that Juno submit, as a Complete Response to the Clinical Hold: a revised patient informed consent form, a revised investigator brochure, a revised trial protocol, and a copy of the presentation made to the agency yesterday. Juno will submit the requested information to the FDA this week.

Juno’s trials and plans for its other CD19-directed CAR-T cell product candidates, including JCAR017, are not affected.

Puma Biotechnology Announces I-SPY 2 Phase II Study of Neratinib Published in The New England Journal of Medicine

On July 7, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported that the positive results from the I-SPY 2 Phase II clinical trial of neratinib for the neoadjuvant treatment of breast cancer were published in the July 7 issue of The New England Journal of Medicine (Press release, Puma Biotechnology, JUL 7, 2016, View Source [SID:1234513761]).

The I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2) is a randomized Phase II clinical trial for women with newly diagnosed Stage 2 or higher (tumor size at least 2.5 cm) breast cancer that addresses whether adding investigational drugs to standard chemotherapy in the neoadjuvant setting is better than standard chemotherapy. The primary endpoint is pathological complete response (pCR) in the breast and the lymph nodes at the time of surgery. The goal of the trial is to match investigational regimens with patient subsets on the basis of molecular characteristics (referred to as biomarker signatures) that benefit from the regimen. The trial enrolled patients who had a high risk of relapse using up-front tumor profiling (including tumor size, hormone receptor status (HR), HER2 status, and the MammaPrint 70-gene signature test).

The I-SPY 2 TRIAL involves an adaptive trial design based on Bayesian predictive probability that a regimen will be shown to be statistically superior to standard neoadjuvant therapy in an equally randomized 300-patient confirmatory trial. Regimens that have a high Bayesian predictive probability of showing superiority in at least one of 10 predefined signatures graduate from the trial. Regimens are dropped for futility if they show a low predictive probability of showing superiority over standard therapy in all 10 signatures. A maximum total of 120 patients can be assigned to each experimental regimen. A regimen can graduate early and at any time after having 60 patients assigned to it.

The neratinib-containing regimen (neratinib plus paclitaxel followed by doxorubicin and cyclophosphamide) graduated from the I-SPY 2 TRIAL based on having a high probability of success in Phase III with a signature of HER2-positive/HR-negative. In this group, treatment with the neratinib-containing regimen resulted in an estimated pCR rate of 55.6% compared to the control arm (standard neoadjuvant chemotherapy: paclitaxel in combination with Herceptin (trastuzumab) followed by doxorubicin and cyclophosphamide) which had an estimated pCR rate of 32.6%. The Bayesian probability of superiority for the neratinib-containing regimen (compared to standard therapy) is 94.9%, which is analogous to a one-sided p-value of 0.051. In addition, the Bayesian predictive probability of showing statistical superiority in a 300-patient Phase III randomized trial of paclitaxel plus neratinib versus paclitaxel plus trastuzumab, both followed by doxorubicin/cyclophosphamide, is 79.1%.

There were 115 patients assigned to neratinib in the trial, including 65 patients who were HER2-positive. For the patients in the trial who were HER2-positive (including those who were either hormone receptor-positive or negative), treatment with the neratinib-containing regimen resulted in an estimated pCR rate of 39.4% compared to the control arm, which demonstrated an estimated pCR rate of 22.8%. The Bayesian probability of superiority for the neratinib-containing regimen is 95.4%, which is analogous to a p-value of 0.046. In addition, the Bayesian predictive probability of showing statistical superiority in a 300-patient Phase III randomized trial of paclitaxel plus neratinib versus paclitaxel plus trastuzumab is 72.7%.

Patients in the I-SPY 2 TRIAL were screened using the MammaPrint 70-gene signature test. The median MammaPrint score from the patients in the previous I-SPY 1 TRIAL who fit the eligibility criteria for I-SPY2 was used as a predefined stratification factor for the I-SPY 2 TRIAL. Patients in I-SPY 2 were stratified as either MammaPrint High (below the median from I-SPY 1) or MammaPrint Ultra High (above the median from I-SPY 1). For the 41 neratinib treated patients in the trial who were MammaPrint Ultra High (80.5% of which were HER2 negative), treatment with the neratinib-containing regimen resulted in an estimated pCR rate of 47.5% compared to the control arm, which demonstrated an estimated pCR rate of 29.4%. The Bayesian probability of superiority for the neratinib-containing regimen is 93.3%, which is analogous to a p-value of 0.067. In addition, the Bayesian predictive probability of showing statistical superiority in a 300-patient Phase III randomized trial of paclitaxel plus neratinib versus paclitaxel, alone for HER2-negative patients or in combination with trastuzumab for the HER2-positive patients, is 71.8%.

The most frequently observed severe adverse event in the trial was diarrhea. In the neratinib treated arm of the trial 38% of the patients experienced grade 3/4 diarrhea while 4% of the patients in the control arm experienced grade 3/4 diarrhea. In several clinical trials subsequent to I-SPY 2, high dose loperamide significantly reduced the incidence of grade 3/4 diarrhea.

The I-SPY 2 TRIAL is a collaborative effort among academic investigators from approximately 20 major cancer research centers across the country, the U.S. Food and Drug Administration, Quantum Leap Healthcare Collaborative, and the Foundation for the National Institutes of Health (FNIH) Cancer Biomarkers Consortium. Major supporters include The Safeway Foundation and the Bill Bowes Foundation.

"I-SPY 2 is an innovative adaptive clinical trial that enabled the investigators to evaluate several agents in the neoadjuvant setting," said Alan H. Auerbach, Chief Executive Officer and President. "We were very pleased with the activity of neratinib in I-SPY 2 as it represents the first clinical data on neratinib in the neoadjuvant treatment of breast cancer and suggests that the combination of paclitaxel plus neratinib has potent activity for the treatment of HER2-positive breast cancer and a subset of patients with HER2-negative breast cancer."

I-SPY 2 Principal Investigators Dr. Laura Esserman, Director of the Carol Franc Buck Breast Care Center and Co-Leader of the Breast Oncology Program at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, and Dr. Donald Berry, Professor of the Department of Biostatistics at the University of Texas MD Anderson Cancer Center, both expressed their enthusiasm for moving successful agents into confirmatory Phase 3 trials. "We are excited for the opportunity to confirm these promising results in I-SPY 3 in our quest to get better treatments to those women who stand to benefit most. I SPY 3 represents a much needed approach to the conduct of Phase 3 trials," said Laura Esserman.