On April 2, 2016 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that interim results from the Phase Ib/II FB-10 clinical trial of Puma’s investigational drug PB272 (neratinib) given in combination with the antibody drug conjugate T-DM1 (Kadcyla, ado-trastuzumab emtansine) 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 2, 2017, View Source [SID1234518392]). The presentation entitled, "NSABP FB-10: Phase Ib dose-escalation study evaluating trastuzumab emtansine (T-DM1) with neratinib in women with metastatic HER2-positive breast cancer" was selected for an oral presentation.

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The trial enrolled patients with HER2-positive metastatic breast cancer who had previously been treated with chemotherapy and the combination of trastuzumab (Herceptin) and pertuzumab (Perjeta). Study treatment consisted of the standard dose of T-DM1 at 3.6 mg/kg administered intravenously every 3 weeks and neratinib administered orally at escalating doses of 120, 160, 200 and 240 mg per day continuously. Primary diarrhea prophylaxis with high dose loperamide was administered.

For the 16 patients who were evaluable for efficacy, the objective response (CR/PR) rate was 56%. More specifically, the efficacy results from the trial demonstrated that 3 patients had a complete response (CR) lasting 17.1 months, 11.9 months and 12+ months; 6 patients had a partial response (PR); 3 patients had stable disease (SD); and 4 patients had progressive disease (PD). The number and types of response per dose cohort are summarized in the table below.


Neratinib Dose
(mg/day)
No. of Objective Responses (CR/PR)
/ No. of Evaluable (CR/PR/SD/PD)
120 5/5 (CR 2, PR 3)
160 2/4 (CR 1, PR 1, PD 2)
200 1/5 (PR 1, SD 2, PD 2)
240 1/2 (PR 1, SD 1)

The waterfall plot for the trial, % Change in Size of Target Lesions," is shown in Figure 1, which is attached to this news release. In addition, the slides from the presentation are available on the Puma Biotechnology website.

The safety results of the study showed that the most frequently observed grade 3 adverse events were diarrhea, nausea, thrombocytopenia and hypertension. More specifically, for the 21 patients with available safety assessments, grade 3 diarrhea was reported in 4 patients (19%), grade 3 nausea was reported in 3 patients (14%), grade 3 thrombocytopenia was reported in 3 patients (14%), and grade 3 hypertension was reported in 2 patients (10%). There was 1 dose limiting toxicity (DLT) at the 120 mg dose (1 of 6 patients), 3 DLTs at the 200 mg dose (3 of 8) and 2 DLTs at the 240 mg dose (2 of 3). Additional patients are currently being accrued at the 160 mg dose in order to define the recommended Phase II dose.

Dr. Jame Abraham, Director of the Breast Oncology Program at Taussig Cancer Institute, Professor of Medicine at Cleveland Clinic, and principal investigator of the study, said, "We are encouraged by these initial findings and we will continue to enroll patients at the 160 mg dose to further evaluate the impact in this patient population."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are pleased to see the high response rate of the combination of T-DM1 and neratinib in this patient population who were previously treated with both pertuzumab and trastuzumab in this study. We look forward to completing enrollment in the current cohort and moving this combination into Phase II trials."

On April 2, 2017 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported that a poster featuring data related to FPA154, Five Prime’s novel tetravalent anti-GITR antibody, was presented today at the 2017 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Washington, D.C (Press release, Five Prime Therapeutics, APR 2, 2017, View Source [SID1234518391]). The poster titled "Development of FPA154, a Novel Tetravalent Anti-GITR Antibody, for the Treatment of Solid Tumors" is available at View Source

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"Our differentiated tetravalent anti-GITR antibody, FPA154, demonstrates activity that appears to be superior to conventional bivalent antibodies," said Luis Borges, Ph.D., Senior Vice President of Research at Five Prime. "These findings suggest our GITR agonist antibody has potent anti-tumor activity for the treatment of cancer, including in combination with PD-1 blockade, which suggests the potential for combination therapy."

Five Prime is developing a novel anti-GITR antibody with enhanced agonist activity for the treatment of solid tumors. Preclinical studies have indicated that GITR-targeting agents inhibit tumor growth via two mechanisms: depletion and possibly suppression of Treg cells and direct agonism of effector T cells. FPA154 recruits antibody-dependent cellular cytotoxicity (ADCC) activity against cells that express high levels of GITR, such as Treg cells within the tumor microenvironment.

A single dose of a mouse-reactive surrogate cmFPA154 molecule demonstrated its ability to induce tumor T cell infiltration and inhibit tumor growth in multiple models. In addition, the surrogate cmFPA154 molecule demonstrated potent anti-tumor activity in combination with PD-1 blockade, even in the absence of Fc effector function, which suggests potential for combination therapy.

On April 2, 2017 Cyclacel Pharmaceuticals, Inc. (NASDAQ:CYCC) (NASDAQ:CYCCP) ("Cyclacel" or the "Company"), reported the presentation by independent investigators of preclinical data demonstrating therapeutic potential of CYC065, the Company’s second-generation, cyclin-dependent kinase (CDK) 2/9 inhibitor, as a targeted anti-cancer agent (Press release, Cyclacel, APR 2, 2017, View Source [SID1234518375]). The data show that CYC065 substantially inhibited growth, triggered apoptosis, and induced anaphase catastrophe in murine and human lung cancer cells with known high metastatic potential. This was in marked contrast to effects in immortalized pulmonary epithelial murine and human cells. CYC065 markedly inhibited migration and invasion of lung cancer cells and affected distinctive pathways involved in DNA damage response, apoptosis, cell cycle regulation and cell migration. The data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2017, April 1 – 5, 2017, in Washington, D.C.

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"This study adds to the growing evidence of the value of CDK inhibition as an approach to treating cancer," said Spiro Rombotis, President and Chief Executive Officer of Cyclacel. "CYC065 is in a Phase 1, first-in-human trial to evaluate safety, tolerability and pharmacokinetics in patients with solid tumors. The trial is at an expanded sixth dose escalation level with the objective of determining maximum tolerated dose and recommended dosing for Phase 2. Evidence of target engagement with prolonged Mcl-1 suppression in peripheral blood cells has been observed in patient samples from the study. We believe that CYC065 is one of the first medicines to demonstrate this in a human trial and look forward to pursuing this lead as part of our transcription regulation program."

In the preclinical study, a group of researchers led by Professor Ethan Dmitrovsky, M.D., including Masanori Kawakami M.D., Ph.D., from The University of Texas MD Anderson Cancer Center, Houston, Texas, explored whether CYC065’s antineoplastic effects engaged anti-metastatic pathways. In vitro migration and invasion assays showed that CYC065 markedly inhibited migration and invasion of lung cancer cell lines, including KRAS mutant line. Reverse Phase Protein Arrays (RPPA) interrogated nearly 300 growth-regulatory proteins in murine and human lung cancer.

CYC065 treatment resulted in up-regulation of proteins involved in DNA damage and apoptosis, and down-regulation of ones involved in mTOR- and integrin pathways. Ingenuity pathway analysis (IPA) revealed up-regulation of pathways that engaged ATM signaling, G2/M DNA damage checkpoint regulation, or apoptosis signaling, down-regulation of pathways involved in mTOR signaling, cell cycle regulation, or integrin—mediated cell migration.

Data presented at AACR (Free AACR Whitepaper) show CYC065’s potential to cause anaphase catastrophe and to inhibit migration and invasion of lung cancer cells including the one with mutant KRAS. Anaphase catastrophe is a novel mechanism of action which offers an innovative approach to combat aneuploid cancer cells containing abnormal numbers of chromosomes. The data highlight CYC065’s potential to target key molecular features of cancers.

The study concluded that CYC065 elicits marked antineoplastic effects in lung cancers despite presence of KRAS mutations through anaphase catastrophe and also inhibited migration and invasion of lung cancer cells.

Abstract: 128
Title: The next generation CDK2/9 inhibitor CYC065 elicits marked antineoplastic effects in lung cancer by engaging anti-metastatic pathways
Date/time: Sunday, April 2, 2017 1:00 — 5:00 p.m. ET
Location: Section 5, Poster Board 24
Session Title:
Novel Agents
Authors: Masanori Kawakami1, Jason Roszik2,3, Lin Zheng1, Jonathan Kurie1, Lisa Maria Mustachio1, Xi Liu1, Ethan Dmitrovsky1 1. Department of Thoracic/Head and Neck Medical Oncology, 2. Genomic Medicine, 3.Cancer Biology; The University of Texas MD Anderson Cancer Center, Houston, Texas.
The abstract can be accessed through the AACR (Free AACR Whitepaper) website, www.aacr.org.

About CYC065

Cyclacel’s second generation CDK2/9 inhibitor, CYC065, is being evaluated in an ongoing, first-in-human, Phase 1 trial in patients with advanced solid tumors. In addition to determining safety and recommended dosing for Phase 2, the study aims to investigate CYC065’s effects on the Mcl-1 biomarker, which is implicated in the evolution of resistance in cancer. Evidence of target engagement with prolonged Mcl-1 suppression in peripheral blood cells was observed in patient samples from the study, as well as decreases in kinase substrate phosphorylation and increases in PARP cleavage, consistently with the Company’s preclinical data. CYC065 is mechanistically similar but has much higher dose potency, in vitro and in vivo, and improved metabolic stability than seliciclib, Cyclacel’s first generation CDK inhibitor. Similar to palbociclib, the first CDK inhibitor approved by FDA in 2015, CYC065 may be most useful as a therapy for patients with both liquid and solid tumors in combination with other anticancer agents, including Bcl-2 antagonists, such as venetoclax, or HER2 inhibitors, such as trastuzumab.

On April 2, 2016 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that results from an ongoing 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 2, 2017, View Source [SID1234518372]). The presentation entitled, "Neratinib in HER2 or HER3 mutant solid tumors: SUMMIT, a global, multi-histology, open-label, phase 2 ‘basket’ study," was presented as a plenary session by David Hyman, M.D., Director of Developmental Therapeutics at Memorial Sloan Kettering Cancer Center (MSK), and principal investigator of the trial.

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The Phase II SUMMIT basket trial is an open-label, multicenter, multinational study to evaluate the safety and efficacy of PB272 administered daily to patients who have solid tumors with activating HER2 or HER3 mutations. All patients received loperamide (16 mg per day initially) prophylactically for the first cycle of treatment in order to reduce the neratinib-related diarrhea.

Included in the presentation were data on 141 patients enrolled in the neratinib monotherapy arm of the trial, including 124 patients with HER2 mutations and 17 patients with HER3 mutations. This included patients with 21 unique tumor types, with the most common being breast, lung, bladder and colorectal cancer. There were also 30 distinct HER2 and 12 distinct HER3 mutations observed among these patients, with the most frequent HER2 variants involving S310, L755, A755_G776insYVMA and V777.

In the HER2-mutant cohort, clinical responses were observed in tumors with S310, L755, V777, P780_Y781insGSP and A775_G776insYVMA mutations. When stratified by tumor type, responses were observed in patients with breast, cervical, biliary, salivary and non-small-cell lung cancers, which led to cohort expansions in these tumor types. No activity was observed in the HER3-mutant cohort. A more detailed presentation of the data is presented in Table 1 below and a copy of the full presentation is available on the Puma Biotechnology website.


Table 1: SUMMIT Trial Efficacy Summary

HER2 mut
HER2 mut
HER2 mut
HER2 mut
HER2 mut
HER2 mut
HER3 mut
Breast Bladder
Lung
Colorectal Biliary tract Cervical NOS
(n=25) (n=16) (n=26) (n=12)

(n=9) (n=5) (n=17)

ORR at week 8,
n (%) 8 (32.0) 0 (0.0) 1 (3.8) 0 (0.0) 2 (22.2) 1 (20.0) 0 (0.0)
(95% CI)
(14.9–53.5) (0.0–20.6) (0.1–19.6) (0.0–26.5) (2.8–60.0) (0.5–71.6) (0.0–20.6)

Clinical benefit
rate, n (%)
10 (40.0) 3 (18.8) 11 (42.3) 1 (8.3) 3 (33.3) 3 (60.0) 2 (11.8)
(95% CI)
(21.1–61.3) (4.0–45.6) (23.4–63.1) (0.2–38.5) (7.5–70.1) (14.7–94.7) (1.6–38.3)

Median PFS,

months 3.5 1.8 5.5 1.8 2.8
20.1
1.7
(95% CI)
(1.9–4.3) (1.7–3.5) (2.7–10.9) (1.4–1.9) (0.5–3.7)
(0.5–NA)
(1.4–2.0)

The neratinib safety profile observed in the SUMMIT study is consistent with that observed previously in metastatic patients with HER2 amplified tumors. With anti-diarrheal prophylaxis and management, diarrhea was not a treatment-limiting side effect in SUMMIT. The interim safety results of the study showed that the most frequently observed adverse event was diarrhea. For the 141 patients enrolled in the neratinib monotherapy arm with safety data available, 31 patients (22%) reported grade 3 diarrhea. The median duration of grade 3 diarrhea for those patients was 2 days. 4 patients (2.8%) permanently discontinued neratinib due to diarrhea and 21 patients (14.9%) temporarily discontinued neratinib due to diarrhea and then restarted after the diarrhea subsided.

Dr. David Hyman stated, "Neratinib showed signs of clinical activity in several of the cohorts in the SUMMIT trial. 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 enrollment in the ongoing cohorts in the study and continuing to utilize the basket trial design to explore possible treatment options for these select patient populations."

"The basket-trial design we are utilizing for SUMMIT is enabling us to evaluate the clinical potential of neratinib in patients with specific mutation-types rather than limiting exploration to one tumor type at a time. It is an efficient approach that is generating clinically meaningful information to guide targeted therapy across a broad spectrum of tumor types with HER mutations, including in patients with rare tumors who may not otherwise have access to investigational therapies," said Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology. "We are very pleased with the preliminary activity seen with neratinib in the SUMMIT trial. We look forward to advancing this targeted compound into further clinical development in multiple HER2 mutant tumor types, both as monotherapy and in novel combinations."

On April 2, 2017 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, has initiated an expanded access program (EAP) in the United States to provide its investigational therapy, PB272 (neratinib), to patients with HER2-positive breast cancer or HER2-mutated cancers (Press release, Puma Biotechnology, APR 2, 2017, View Source [SID1234518371]).

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The program will provide access to neratinib for the treatment of early stage HER2-positive breast cancer (extended adjuvant setting), HER2-positive metastatic breast cancer and HER2-mutated solid tumors. Patients must not be able to participate in any ongoing neratinib clinical trial to qualify for Puma’s expanded access program. Puma announced a Managed Access Program for neratinib outside the United States in the fourth quarter of 2016.

The U.S. Food and Drug Administration (FDA) permits expanded access to investigational drugs for treatment use for patients with serious or immediately life-threatening diseases or conditions who do not otherwise qualify for participation in a clinical trial and lack satisfactory therapeutic alternatives.

Caligor Opco LLC, which administers the Managed Access Program for neratinib, also will manage the U.S. expanded access program by providing regulatory and logistical support.

"This expanded access program reflects our commitment to make neratinib available to eligible patients who lack therapeutic treatment options," said Alan H. Auerbach, Chief Executive Officer and President of Puma. "As a specialist firm that focuses on early access to medicines, Caligor will facilitate access to neratinib for patients who may benefit from this therapy."

About the Neratinib Expanded Access Program

The neratinib EAP is a program for U.S. patients with early stage HER2-positive breast cancer (extended adjuvant setting), HER2-positive metastatic breast cancer and HER2-mutated solid tumors. This EAP is being administered on behalf of Puma by Caligor Opco LLC. U.S. healthcare professionals seeking more information about the neratinib EAP can email [email protected] for additional information. Patients who are interested in enrolling in the neratinib EAP should speak with their physician to determine if neratinib is an appropriate option. Neratinib is an investigational agent and, as such, has not been approved by the FDA or any other regulatory agencies in any markets.

About Caligor

Caligor Opco LLC, a portfolio company of Diversis Capital, LLC, is a global company that manages the regulatory, logistics and supply chain needs for global access programs as well as the sourcing, storing and distribution of comparator drugs for clinical trials. Caligor’s global access programs help to meet the medical needs of patients worldwide by providing access to medicines in situations where the drug has not yet been approved, or is otherwise commercially unavailable. In addition, through its proprietary TrialAssist program, Caligor optimizes its services by providing for labeling, QP certification, storage, distribution and destruction of clinical trial and unlicensed medicines managed in the access programs. The company serves pharmaceutical and biotechnology companies from facilities in Secaucus, New Jersey and Dartford, UK, as well as strategically situated depot locations worldwide. More information is available at View Source