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.

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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

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.

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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.

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]).

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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.