On June 1, 2015 Baxter Ventures, the venture arm of Baxter International Inc. (NYSE:BAX), the Mayo Clinic and Velocity Pharmaceutical Development, LLC ("VPD") reported the formation of Vitesse Biologics, LLC, ("Vitesse") (Press release, Velocity Pharmaceutical Development, JUN 1, 2015, View Source [SID:1234506532]). Vitesse is a unique collaboration model initiated by Baxter Ventures to focus on the development of antibody and protein-based therapeutics in the areas of immunology, hematology, and oncology. Following the spin-off of Baxter BioScience as Baxalta Incorporated, anticipated to take place by mid-2015, the Vitesse relationship will be managed by the planned venture arm, Baxalta Ventures, for the new company.

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The collaboration model, which represents a new method of drug development, was designed to incent each partner to advance promising therapies quickly through the development process. Each partner will provide its recognized expertise to enhance the target selection, target optimization, expression and product development process. Baxter BioScience will provide global commercialization, antibody and protein development and manufacturing capabilities; Mayo Clinic researchers will execute the Phase I clinical trials; VPD will be responsible for target identification, selection of early stage drug candidates and will lead the design and execution of pre-clinical and clinical protocols.

"Delivering innovative treatments to address unmet patient needs is at the very core of everything we do and drives our ongoing R&D focus," said Ludwig N. Hantson, Ph.D., president of Baxter BioScience. "By creating Vitesse, our business is executing on a new concept in early stage R&D by leveraging the expertise of industry-leading partners to accelerate the identification and development of novel biologic treatments that could eventually contribute to unmet patient needs while enhancing the Baxalta commercial portfolio."

Vitesse will develop treatments in the fields of hematology, oncology and immunology, which aligns strongly with Baxter BioScience’s therapeutic focus. This innovative model enables Baxter to serve as a hands-on partner in the pursuit of innovative treatments, as Baxter BioScience will be involved in the early-stages of development for all products identified by Vitesse and has an exclusive option to acquire each such product following the completion of the applicable Phase I trials.

"We are excited about the possibilities for this new collaboration, and particularly for this new model for early stage drug development," said Greg Gores, M.D., executive dean for research at Mayo Clinic. "Our goal is to identify new, useful therapeutics to address the unmet needs of our patients."

David Collier, M.D., CEO of VPD, said, "We are fortunate to have world-class partners in this project. We believe that the combination of the development and manufacturing expertise offered by Baxter BioScience and the clinical capabilities of the Mayo Clinic, working in conjunction with our team at VPD, will produce a series of very promising new therapeutics developed in a more rapid and cost-efficient manner."

With research as a key priority of the Destination Medical Center (DMC) initiative, Mayo Clinic is building upon the clinical and research infrastructure further accelerating Mayo Clinic’s ability to conduct some of the most important medical research, eventually to translate these discoveries into therapies for patients from across the globe.

ABOUT VITESSE BIOLOGICS, LLC Vitesse Biologics, LLC, a Delaware Corporation based in South San Francisco, CA, develops antibody and protein-based therapeutics in the areas of immunology, hematology, and oncology.

On June 1, 2015 Janssen Research & Development reported data from the Phase 3 multicenter study SAR3007, which demonstrated a significant improvement in progression-free survival (PFS) with trabectedin (YONDELIS) compared to dacarbazine in patients with advanced liposarcoma (LPS) or leiomyosarcoma (LMS) previously treated with an anthracycline and at least one additional chemotherapy regimen (Press release, Johnson & Johnson, JUN 1, 2015, View Source [SID:1234505209]). SAR3007 is the largest randomized Phase 3 study ever conducted in this patient population. These data were presented today in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL.

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Soft tissue sarcoma (STS) is a type of cancer originating in the soft tissues that connect, support and surround other body structures, such as muscle, fat, blood vessels, nerves, tendons and the lining of joints.[1],[2] LPS and LMS are among the most common types of STS in adults and represent approximately 40-50% of all STS cases.[3],[4]

"Advanced soft tissue sarcomas represent a complex set of rare diseases which, when advanced, are life threatening. Our patients need new treatment options that are effective and reasonably well tolerated, as the treatment landscape has been relatively stagnant for decades," said George Demetri, M.D., Director, Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute and Professor at Harvard Medical School. "In soft tissue sarcomas, disease stabilization is an important metric for evaluating treatment success in patients with advanced disease. The safety data from this trial were consistent with the well-defined adverse events observed in previous clinical trials of trabectedin and in clinical use outside the United States where trabectedin has been approved to treat these aggressive diseases."

Trabectedin is approved in 77 countries in North America, Europe, South America and Asia under the trade name YONDELIS for the treatment of advanced STS as a single agent. Janssen submitted a New Drug Application for YONDELISto the U.S. Food and Drug Administration on November 24, 2014, which was granted Priority Review on February 3, 2015.

"The data presented at ASCO (Free ASCO Whitepaper) underscore the value of trabectedin as a potentially important treatment option for patients with LPS and LMS subtypes of soft tissue sarcoma," said Craig Tendler, M.D., Vice President, Late Development and Global Medical Affairs, Oncology, Janssen. "This latest research underlines our long-standing commitment to patients with advanced soft tissue sarcoma. To date, more than 50,000 patients worldwide have been treated with YONDELIS, including approximately 3,000 patients in our Expanded Access Program in the United States."

In this randomized, active-controlled Phase 3 study in patients with advanced LPS or LMS, trabectedin significantly reduced the risk of disease progression or death by 45% compared with those who received dacarbazine (hazard ratio [HR] = 0.550; P< 0.0001; median [M] 4.2 vs. 1.5 months, respectively), with results validated through an audit by independent radiologists. The improved PFS benefit with trabectedin treatment was consistently observed across all clinically relevant subgroups and was further supported by an increased objective response rate (ORR), a longer duration of response (DOR), and a higher clinical benefit response rate as compared to dacarbazine. At the interim analysis for overall survival (OS), the trial had not met the primary endpoint of OS. The study is ongoing to determine the final OS results, which will be presented at a future meeting. The results for the secondary efficacy endpoints are mature.

Safety findings were consistent with the well-characterized safety profiles of both agents, with the most common Grade 3-4 toxicities in the trabectedin versus the dacarbazine groups being decreased absolute neutrophil count (40% vs. 25%), decreased platelets (19% vs. 20%), and transient increases in liver transaminases, including alanine transaminase (ALT) (29% vs. 1%). Drug-related deaths occurred in 2.1% of patients in the trabectedin group versus 0% of patients in the dacarbazine group.

About SAR3007

The Phase 3 multicenter study SAR3007 compared trabectedin with dacarbazine in patients with advanced LPS or LMS previously treated with an anthracycline and at least one additional chemotherapy regimen. The primary endpoint is OS and secondary endpoints included PFS, time to progression (TTP), ORR, DOR, symptom severity and safety. Both treatments were administered via an IV infusion every three weeks with the trabectedin dose of 1.5 mg/m2 given over 24 hours versus dacarbazine dose of 1 g/m2 given over 20-120 minutes. Ninety-four percent of study participants were in the United States.

About Soft Tissue Sarcoma

Soft tissue sarcoma is a type of cancer originating in the soft tissues that connect, support and surround other body structures, such as muscle, fat, blood vessels, nerves, tendons and the lining of joints.1,2 In the United States, nearly 12,000 people will be diagnosed and approximately 4,870 are expected to die of soft tissue sarcomas in 2015.[5] Leiomyosarcoma is an aggressive type of soft tissue sarcoma that occurs in smooth muscles, such as those in the uterus, gastrointestinal tract or lining of blood vessels.[6] Liposarcoma originates in fat cells and most commonly occurs in the thigh and abdominal cavity, though it can occur in fat cells in any part of the body.[7],[8]

About YONDELIS (trabectedin)
YONDELIS (trabectedin) is a novel, multimodal, synthetically produced antitumor agent, originally derived from the sea squirt, Ecteinascidia turbinata. The anti-cancer medicine works by preventing the tumor cells from multiplying and is approved in 77 countries in North America, Europe, South America and Asia for the treatment of advanced soft tissue sarcoma as a single agent, and in 70 countries for relapsed ovarian cancer in combination with DOXIL/CAELYX (doxorubicin HCl liposome injection).

Under a licensing agreement with PharmaMar, a wholly owned member of the Zeltia Group, Janssen Products, LP has the rights to develop and sell YONDELIS globally except in Europe, where PharmaMar SA holds the rights, and in Japan, where PharmaMar has granted a license to Taiho Pharmaceuticals Co., Ltd. If approved in the United States, YONDELIS would be commercialized by Janssen Biotech, Inc.

On May 31, 2015 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported new results from the Phase II NeoSphere study (Press release, Genentech, MAY 31, 2015, View Source [SID:1234506558]). The results suggested that Perjeta (pertuzumab) in combination with Herceptin (trastuzumab) and docetaxel chemotherapy given prior to surgery reduced the risk of disease getting worse and increased the time people lived without their cancer returning compared to Herceptin and chemotherapy in people with HER2-positive early breast cancer (eBC). The safety profile of the Perjeta regimen was consistent with that seen in previous studies, and no new safety signals were identified. These data will be presented today at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago by Dr. Luca Gianni, Medical Oncology, San Raffaele Hospital, Scientific Institute (Abstract #505).

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In the NeoSphere study, both progression-free survival (PFS) and disease-free survival (DFS) were evaluated at three years. The results suggested that people who received the Perjeta regimen prior to surgery were 31 percent less likely to experience disease worsening, recurrence or death (PFS HR=0.69; 95% CI, 0.34–1.40) compared to those who received Herceptin and chemotherapy. People treated with the Perjeta regimen were also 40 percent less likely to experience disease recurrence or death (DFS HR=0.60; 95% CI, 0.28–1.27). People in the NeoSphere study who were treated in the neoadjuvant setting also received a year of adjuvant treatment with Herceptin plus chemotherapy after their surgery. The results of this analysis are descriptive, as the study was not designed to show statistical significance for three-year PFS and DFS.

"Treating breast cancer early, before it has spread, may help prevent the disease from returning or reaching an advanced stage," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "These new results add to the body of data for Perjeta in the neoadjuvant setting, and we look forward to the Phase III APHINITY study results to better understand the broader impact of Perjeta in the adjuvant treatment of HER2-positive early breast cancer."


The results also suggested that people who achieved pathological complete response (pCR; no tumor tissue detectable at the time of surgery in the affected breast and local lymph nodes) were more likely across all arms of the study to be alive and disease-free at three years (PFS HR=0.54; 95% CI, 0.29–1.00; DFS HR=0.68; 95% CI, 0.36–1.26). It was previously reported that the Perjeta regimen significantly increased the number of people who achieved pCR compared to Herceptin and docetaxel chemotherapy (39.3 vs. 21.5 percent).

In 2013, the U.S. Food and Drug Administration (FDA) granted accelerated (or "conditional") approval of the Perjeta regimen for neoadjuvant treatment in people with 
high-risk, HER2-positive eBC. A full review of data from the ongoing Phase III APHINITY study will be required for the accelerated approval to be converted to a full approval. APHINITY compares Perjeta, Herceptin and chemotherapy with Herceptin and chemotherapy for adjuvant (post-surgery) treatment in people with HER2-positive eBC. Data from APHINITY are expected in 2016.

Roche recently submitted a Marketing Authorization Application to the European Medicines Agency (EMA) for the Perjeta regimen as a neoadjuvant treatment for people with HER2-positive eBC.

About the NeoSphere Trial

The NeoSphere trial (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) is a randomized, multicenter, international Phase II study in 417 people with newly diagnosed HER2-positive, operable, locally advanced, or inflammatory eBC. Participants were randomized to one of four study arms and received four cycles (12 weeks) of neoadjuvant treatment followed by surgery and a year of adjuvant treatment with Herceptin plus chemotherapy. The primary endpoint was pCR. Secondary endpoints included clinical response, time to clinical response, safety profile, PFS, DFS, 
breast-conserving surgery rate and biomarker assessment.

These new data suggested:

PFS rate at three years was 90 percent in the Perjeta arm compared to 86 percent in the Herceptin and docetaxel chemotherapy arm (HR=0.69).

DFS rate was 92 percent in people who received the Perjeta regimen compared to 85 percent in people who received Herceptin and chemotherapy (HR=0.60).

The safety profile was consistent with previous studies of Perjeta, and no new safety signals were identified.
Previously reported data from the primary analysis showed:

Treatment with Perjeta, Herceptin and docetaxel chemotherapy significantly improved the rate of pCR in the affected breast and local lymph nodes by 17.8 percent compared to Herceptin and chemotherapy alone (39.3 vs. 21.5 percent, p=0.0063).
pCR of 21.5 percent for Herceptin and chemotherapy
pCR of 39.3 percent for Perjeta, Herceptin and chemotherapy
pCR of 11.2 percent for Perjeta and Herceptin
pCR of 17.7 percent for Perjeta and chemotherapy

The Perjeta regimen was not associated with a significant increase in adverse events (AEs), compared to Herceptin and chemotherapy alone.

The most common severe (Grade 3 or higher) AEs for the Perjeta regimen were neutropenia (decrease in a certain type of white blood cell, 44.9 percent), febrile neutropenia (fever associated with decrease in a certain type of white blood cell, 8.4 percent), leukopenia (decrease in overall white blood cells, 4.7 percent) and diarrhea (5.6 percent).

About Perjeta

Perjeta is a medicine that targets the HER2 receptor, a protein found on the outside of many normal cells and in high quantities on the outside of cancer cells in HER2-positive cancers. Perjeta is designed specifically to prevent the HER2 receptor from pairing (or "dimerizing") with other HER receptors (EGFR/HER1, HER3 and HER4) on the surface of cells, a process that is believed to play a role in tumor growth and survival. Binding of Perjeta to HER2 may also signal the body’s immune system to destroy the cancer cells. The mechanisms of action of Perjeta and Herceptin are believed to complement each other, as both bind to the HER2 receptor, but to different places. The combination of Perjeta and Herceptin is thought to provide a more comprehensive blockade of HER signaling pathways, thus preventing tumor cell growth and survival.


Perjeta Indication Statements

Perjeta is approved for use in combination with Herceptin and docetaxel chemotherapy in people who have HER2-positive breast cancer that has spread to different parts of the body (metastatic) and who have not received anti-HER2 therapy or chemotherapy for metastatic breast cancer.

Perjeta is approved for use prior to surgery in combination with Herceptin and docetaxel chemotherapy in people with HER2-positive, locally advanced, inflammatory, or early stage (tumor is greater than two centimeters in diameter or node positive) breast cancer. Perjeta should be used as part of a complete treatment regimen for early stage breast cancer. This use of Perjeta is based on an improvement in the percentage of people who had no evidence of cancer in the breast or lymph nodes at the time of surgery. Currently, no data have shown whether or not treatment with Perjeta prior to surgery improves survival. The safety of Perjeta as part of a doxorubicin (chemotherapy)-containing regimen has not been established. The safety of Perjeta administered for greater than six cycles for early stage breast cancer has not been established.

Important Safety Information

Perjeta may cause heart problems, including those without symptoms (such as reduced heart function) and those with symptoms (such as congestive heart failure).

A patient’s doctor may run tests to monitor the patient’s heart function before and during treatment with Perjeta.
Based on test results, the doctor may decide to hold or discontinue treatment with Perjeta.

Receiving Perjeta during pregnancy can result in the death of an unborn baby and birth defects.

Birth control should be used while receiving Perjeta and for seven months after a patient’s last dose of Perjeta. If a patient is a mother who is breastfeeding, the patient should talk with her doctor about either stopping breastfeeding or stopping Perjeta.
If a patient thinks she may be pregnant, the patient should contact their healthcare provider immediately.

If a patient is exposed to Perjeta during pregnancy or within seven months of becoming pregnant, the patient is encouraged to enroll in the MotHER Pregnancy Registry by contacting (800) 690-6720.

Perjeta should not be used in patients who are allergic to pertuzumab or to any of the ingredients in Perjeta.

Other possible serious side effects of Perjeta therapy include:

Infusion-related reactions: Perjeta is a medicine that is delivered into a vein through a needle. This process can cause reactions known as infusion-related reactions. The most common infusion-related reactions when receiving Perjeta, Herceptin and docetaxel chemotherapy were feeling tired, abnormal or altered taste, allergic reactions, muscle pain and vomiting. The most common infusion-related reactions when receiving Perjeta alone were fever, chills, feeling tired, headache, weakness, allergic reactions and vomiting.

Severe allergic reactions: Some people receiving Perjeta may have severe allergic reactions, called hypersensitivity reactions or anaphylaxis. This reaction may be severe, may happen quickly and may affect many areas of the body.

Perjeta has only been shown to work in people with HER2-positive breast cancer.

The most common side effects of Perjeta when given with Herceptin and docetaxel chemotherapy for treatment of breast cancer that has spread to other parts of the body (metastatic) are:

Diarrhea
Hair loss
Low levels of white blood cells with or without a fever
Nausea
Feeling tired
Rash
Damage to the nerves (numbness, tingling, pain in hands/feet)

The most common side effects of Perjeta when given with Herceptin and docetaxel chemotherapy as part of an early stage breast cancer regimen before surgery are:

Hair loss
Diarrhea
Nausea
Low levels of white blood cells with or without a fever

The most common side effects of Perjeta when given with Herceptin and docetaxel chemotherapy following three cycles of epirubicin, cyclophosphamide and fluorouracil as part of an early stage breast cancer regimen before surgery are:

Feeling tired
Hair loss
Diarrhea
Nausea
Vomiting
Low levels of white blood cells with or without a fever

The most common side effects of Perjeta when given with Herceptin, docetaxel chemotherapy and carboplatin chemotherapy as part of an early stage breast cancer regimen before surgery are:

Feeling tired
Hair loss
Diarrhea
Nausea
Vomiting
Low levels of white blood cells with or without a fever
Low platelet count
Low levels of red blood cells

Report side effects to Genentech and the FDA. Report side effects to the FDA at (800) FDA-1088 or View Source Report side effects to Genentech at (888) 835-2555.

Please see Perjeta full Prescribing Information including Most Serious Side Effects for additional Important Safety Information at View Source

About Breast Cancer

Breast cancer is the most common cancer among women worldwide. According to the American Cancer Society, approximately 234,000 people in the United States will be diagnosed with breast cancer, and 41,000 will die from the disease in 2015. In HER2-positive breast cancer, increased quantities of the Human Epidermal growth factor Receptor 2 (HER2) are present on the surface of the tumor cells. This is known as "HER2 positivity" and affects approximately 20-25 percent of people with breast cancer. HER2-positive cancer is a particularly aggressive form of breast cancer.

On June 1, 2015 Boston Biomedical reported Boston Biomedical will present clinical data today on the investigational compounds BBI608 and BBI503 in multiple tumor types at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting in Chicago (Press release, Dainippon Sumitomo Pharma, MAY 31, 2015, View Source [SID:1234505206]).

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Data presented at ASCO (Free ASCO Whitepaper) highlight the potential of BBI608—an orally-administered investigational agent that targets STAT3, leading to inhibition of the critical genes for maintaining cancer stemness—for anti-cancer activity when used in combination with other chemotherapeutics across varying advanced cancers, including gastric and colorectal. Additionally, as part of the "trials in progress" program, the study protocol from the BRIGHTER study, a phase 3 clinical trial currently underway to investigate cancer stem cell pathway inhibition, is also showcased.

"Recurrence and metastasis remain clinically challenging for oncologists, and require novel treatment advancements to ensure more durable and sustained responses for cancer patients," said Manish A. Shah, M.D., the Director of Gastrointestinal Oncology at New YorkPresbyterian/Weill Cornell Medical Center, Weill Cornell Medical College. "The BBI608 data indicate encouraging early signs of clinical activity, and support the expansive BBI608 clinical development plan including the phase 3 BRIGHTER trial in advanced gastric/gastroesophageal junction cancer."

Additional data featuring BBI503—an orally-administered investigational agent designed to inhibit Nanog and other cancer stem cell pathways by targeting kinases—showed encouraging early signs of anti-cancer activity for patients with advanced colorectal cancer.

Boston Biomedical poster presentations include:

Abstract #4069, Poster #179: BBI608-201: Phase 1b/2 study of cancer stemness inhibitor BBI608 combined with paclitaxel in advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma
• Data from the study showed BBI608 and weekly paclitaxel can be combined in patients with advanced pre-treated gastric/GEJ cancer. Lesion regression, objective responses, and prolonged stable disease were observed in heavily pre-treated patients.

In evaluable patients who had not previously received a taxane in the metastatic setting, and who received one prior line of therapy (n=6), namely the patients that meet the enrollment criteria for the BRIGHTER trial, an objective response rate (ORR) of 50% was observed. 2 In heavily pretreated patients (failed average >2 lines of prior therapies) who had not previously received a taxane in the metastatic setting (n=16), the ORR was 31% in the per-protocol population. The disease control rate (DCR) was 75%; median progressionfree survival (mPFS) was 20.6 weeks and median overall survival (mOS) was 39.3 weeks.

Most common adverse events were grade 1 to 2 diarrhea, nausea, vomiting and abdominal pain. Grade 3 adverse events included vomiting (8.7%), diarrhea of 5 days or longer (6.5%), fatigue (6.5%), abdominal and gastrointestinal pain, nausea, dehydration, anorexia, white blood cell decrease and acute kidney injury (2.2% each).

Continued evaluation of this combination and patient population, specifically in those patients who received one prior line of therapy, is currently underway in the phase 3 BRIGHTER study

Abstract #TPS4139, Poster #247a: The BRIGHTER trial: A phase 3 randomized, doubleblind, placebo-controlled clinical trial of first-in-class cancer stemness inhibitor BBI608 plus weekly paclitaxel versus placebo plus weekly paclitaxel in adult patients with advanced, previously treated gastric and gastro-esophageal junction (GEJ) adenocarcinoma
• The goal of the BRIGHTER trial (NCT02178956) is to determine if BBI608 given together with paclitaxel as second-line therapy will extend survival compared to treatment with paclitaxel alone. Enrollment is ongoing at multiple sites in North America, Europe, Australia and Japan. BBI608 blocks cancer stem cell renewal and survival by suppressing stemness pathways, including STAT3, â-catenin and immune checkpoint gene expression.

Abstract #3616, Poster #109: BBI608-246: A phase 1b study of first-in-class cancer stemness inhibitor BBI608 in combination with FOLFIRI with and without Bevacizumab in patients with advanced colorectal cancer
• Data from the study showed that BBI608 at 240 mg BID can be combined with FOLFIRI, with or without bevacizumab, in patients with advanced and heavily pretreated colorectal cancer (CRC).

Disease control, measured by partial response and stable disease, was observed in 100% of evaluable patients (n=9), including 6 patients who had failed FOLFIRI previously, with partial response in 2/9 patients and stable disease in 7/9 patients, all of whom (9/9 patients) experienced signs of tumor regression. Prolonged stable disease (more than or equal to 6 months) was observed in 5/9 patients (55.6%) of evaluable patients. The median progression-free survival was 23.7 weeks.

Most common adverse events included grade 1 and 2 diarrhea, fatigue, anorexia, nausea, vomiting and abdominal pain. Grade 3 diarrhea was observed in two patients, and resolved with a brief BBI608 dose holiday or dose reduction and anti-diarrheal medications, respectively. Additionally, self-resolving grade 3 fatigue lasting 4-8 days as well as dehydration was observed in one patient.

Abstract #3617, Poster #110: BBI608-224: A phase 1b/2 study of cancer stemness inhibitor BBI608 administered with Panitumumab in KRAS wild-type patients with metastatic colorectal cancer
• Results from the study found that BBI608 and bi-weekly panitumumab can be combined at the full dose of 480-500 mg BID.

Of the 24 patients enrolled, nine were anti-EGFR naïve and 15 had previously failed anti-EGFR therapy. Disease control, measured by stable disease and partial response, was observed in 44% of anti-EGFR naïve patients compared to 53.3% of patients who had failed anti-EGFR therapy previously. The median progression-free survival was 9 weeks in anti-EGFR naïve patients.

Also in this study, preliminary activity was observed in K-Ras wild-type mCRC patients regardless of prior anti-EGFR exposure, suggesting BBI608 may have re-sensitized patients to repeat anti-EGFR therapy.

Most common adverse events included grade 1-2 diarrhea, nausea, fatigue, vomiting, abdominal cramping, hypokalemia and anorexia. Grade 3 hypokalemia and diarrhea occurred in three patients, as well as abdominal pain, fatigue, hypomagnesemia, hypophosphatemia and rash in one patient.

Further studies are needed to evaluate the safety and efficacy of this combination and BBI608’s potential to re-sensitize patients to anti-EGFR therapy. Encouraging signs of activity were also observed in anti-EGFR naive patients.

Abstract #3615, Poster #108: BBI503-101: Phase 1 extension study of BBI503, a first-inclass cancer stemness kinase inhibitor, in patients with advanced colorectal cancer
• The findings indicated that BBI503 as a monotherapy was tolerated at the recommended phase 2 dose of 300 mg once daily.

Disease control rate (DCR), comprising complete response, partial response and stable disease measures, in evaluated patients with high Nanog biomarker-positive status was 55.6%, while DCR in biomarker-negative patients was 12.5%.
Median overall survival in biomarker-positive patients was 38.0 weeks compared to 15.9 weeks in biomarkernegative patients.

At the recommended phase 2 dose, common adverse events were grade 1 to 2 diarrhea, nausea, abdominal cramping, anorexia and fatigue, and grade 3 adverse events were fatigue (n= 4), and diarrhea, nausea, and weight loss (n=1 each)

This study underscores that further clinical evaluation of BBI503 alone or in combination with standard chemotherapeutic agents in advanced colorectal cancer is warranted. Also, findings from a publication-only abstract are available:

Abstract #e15089: A phase 1 study of BBI608, a cancer stemness inhibitor, administered with paclitaxel (PTX) as combination therapy (Rx) for pretreated unresectable or recurrent gastric cancer in Japan
• This study showed that BBI608 plus paclitaxel can be combined in patients with advanced gastric/gastroesophageal junction adenocarcinoma (n=6). 4

Two patients (33.3%) achieved a partial response (66.7% and 36.8% regression), and one of them maintained response for more than seven and a half months. Two additional patients achieved stable disease at 2.8 months.

Most common adverse events were grade 1 diarrhea and anorexia. No severe side effects were observed in this study.

"It is an exciting time for Boston Biomedical as we showcase a broad array of studies for cancer stem cell pathway inhibitors BBI608 and BBI503 and share additional details about our pioneering phase 3 BRIGHTER study," said Chiang J. Li, M.D. FACP, the president, CEO and Chief Medical Officer of Boston Biomedical, and the Head of Global Oncology for Sumitomo Dainippon Pharma Group. "The efficacy and safety results from these studies build upon the already encouraging foundation of clinical evidence, and support the need to further research these potential first-in-class treatment options."

On May 31, 2015 Gilead Sciences, Inc. (Nasdaq:GILD) reported results from the Phase 3 clinical Study 119 of an investigational use of Zydelig (idelalisib) in combination with ofatumumab in previously-treated patients with chronic lymphocytic leukemia (CLL) (Press release, Gilead Sciences, MAY 31, 2015, View Source;p=irol-newsArticle&ID=2054590 [SID:1234506559]). In Study 119, there was a 73 percent reduction in the risk of disease progression or death in patients receiving Zydelig in combination with ofatumumab compared to ofatumumab alone (hazard ratio (HR) = 0.27; 95 percent CI: 0.19, 0.39; p<0.0001). Detailed results will be presented today during a poster session at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Abstract #7023).

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"The data reported today reinforce prior results showing that idelalisib, here in combination with the anti-CD20 monoclonal antibody ofatumumab, not only significantly improved overall and lymph node response rates, but more importantly progression-free survival in patients with previously treated CLL," said Jeffrey A. Jones, MD, MPH, Associate Professor of Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James). "Importantly, these improvements were also observed in patients with genetic features typically associated with poor prognosis."

Study 119 was a randomized, controlled, open-label Phase 3 study evaluating the efficacy and safety of Zydelig in combination with ofatumumab. The study enrolled 261 adult patients with previously treated CLL whose disease had progressed less than 24 months following completion of prior therapy, and had not previously been refractory to ofatumumab. Eligible patients were randomized 2:1 to receive an ofatumumab 1,000 mg dosing regimen (12 infusions, first infusion 300mg) over 24 weeks plus Zydelig (150 mg) twice daily (n=174) continuously until disease progression or unacceptable toxicity or an ofatumumab 2,000 mg dosing regimen (12 infusions, first infusion 300mg) over 24 weeks (n=87).

The primary endpoint was progression-free survival (PFS), defined as the time from randomization to definitive disease progression or death assessed by an independent review committee. Median PFS in the Zydelig/ofatumumab arm was 16.3 months, compared to 8.0 months in the ofatumumab monotherapy arm. Statistically significant improvements were also observed for overall response rate (75 percent vs. 18 percent; odds ratio (OR) = 15.9, p<0.0001) and lymph node response rate (93.3 percent vs. 4.9 percent; OR=486.96, p<0.0001). Median PFS in the approximately 40 percent of patients with 17p deletion or TP53 mutation was 13.7 months vs. 5.8 months (HR=0.32, p<0.0001). A statistically significant difference was not achieved in median overall survival (20.9 months vs. 19.4 months; HR=0.74, p=0.27).

The safety profile of Zydelig was similar to prior studies in previously-treated patients with CLL. Grade ≥3 adverse events occurring in the Zydelig plus ofatumumab arm included diarrhea/colitis (20.2 percent), pneumonia (12.7 percent) and febrile neutropenia (11.6 percent).

Based on the Study 119 trial results, Gilead has filed a supplemental New Drug Application (sNDA) with the U.S. Food and Drug Administration to include data from this study in the U.S. label. Gilead plans to submit a supplemental filing to the European Medicines Agency later this year.

"Zydelig has now demonstrated strong efficacy in two randomized Phase 3 studies among previously treated CLL patients," said Norbert Bischofberger, PhD, Gilead’s Executive Vice President, Research and Development and Chief Scientific Officer. "We continue to explore the clinical profile of Zydelig in combination with both standard and novel treatment regimens, including seven ongoing or completed Phase 3 clinical trials for B-cell malignancies."

The Zydelig U.S. Prescribing Information includes a BOXED WARNING regarding fatal and serious toxicities of hepatotoxicity, severe diarrhea/colitis, pneumonitis, and intestinal perforation; see below for Important Safety Information.

The use of Zydelig in combination with ofatumumab is investigational and the safety and efficacy of this combination has not yet been established.

Dr. Jones is an uncompensated advisory board member to Gilead and receives research grant support to support this Phase 3 trial at The OSUCCC – James.

About Zydelig (idelalisib)

Zydelig is an oral inhibitor of phosphoinositide 3-kinase (PI3K) delta, a protein that plays a role in the activation, proliferation and viability of B cells, a critical component of the immune system. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and by inhibiting the protein, Zydelig blocks several cellular signaling pathways that drive B-cell viability.

On July 23, 2014, Zydelig received accelerated approval from the U.S. Food and Drug Administration as monotherapy for patients with relapsed follicular lymphoma (FL) or small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies, and full approval in combination with rituximab for patients with relapsed CLL for whom rituximab alone would be considered appropriate therapy due to comorbidities. On September 19, 2014, the European Commission granted marketing authorization for Zydelig as monotherapy in FL patients who are refractory to two prior lines of treatment, and in combination with rituximab for CLL patients who have received at least one prior therapy, or in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemoimmunotherapy.

Additional information about clinical studies of Zydelig and Gilead’s investigational cancer agents can be found at www.clinicaltrials.gov.

Important U.S. Safety Information

BOXED WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS AND INTESTINAL PERFORATION

Fatal and/or serious hepatotoxicity occurred in 14 percent of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig as recommended.

Fatal and/or serious and severe diarrhea or colitis occurred in 14 percent of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig as recommended.

Fatal and serious pneumonitis can occur. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig as recommended.

Fatal and serious intestinal perforation can occur in Zydelig-treated patients. Discontinue Zydelig for intestinal perforation.

Contraindications

History of serious allergic reactions, including anaphylaxis and toxic epidermal necrolysis (TEN).
Warnings and Precautions

Hepatotoxicity: Findings were generally observed within the first 12 weeks of treatment and reversed with dose interruption. Upon rechallenge at a lower dose, ALT/AST elevations recurred in 26% of patients. In all patients, monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, and every 1 to 3 months thereafter. If ALT/AST is >3x upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5x ULN, withhold Zydelig and monitor ALT/AST and total bilirubin weekly until resolved. Discontinue Zydelig for recurrent hepatotoxicity. Avoid concurrent use with other hepatotoxic drugs.
Severe diarrhea or colitis: Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents. Avoid concurrent use with other drugs that cause diarrhea.

Pneumonitis: Evaluate for pneumonitis in patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by ≥5 percent

Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting.

Severe cutaneous reactions: One case of TEN occurred in a study of Zydelig in combination with rituximab and bendamustine. Other severe or life-threatening (grade ≥3) cutaneous reactions have been reported. Monitor patients for the development of severe cutaneous reactions and discontinue Zydelig if a reaction occurs.

Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported. Discontinue Zydelig permanently and institute appropriate supportive measures if a reaction occurs.

Neutropenia: Treatment-emergent grade 3-4 neutropenia occurred in 31 percent of Zydelig-treated patients in clinical trials. In all patients, monitor blood counts ≥every 2 weeks for the first 3 months. In patients with neutrophil counts <1.0 Gi/L, monitor weekly.

Embryo-fetal toxicity: Zydelig may cause fetal harm. Women who are or become pregnant while taking Zydelig should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Zydelig and to use effective contraception during and at least 1 month after treatment with Zydelig.

Adverse Reactions

Most common adverse reactions (incidence ≥10 percent and ≥2 percent than rituximab alone, all grades) were pyrexia, nausea, pneumonia, diarrhea, chills, rash, vomiting and headache.

Most frequent serious adverse reactions (SAR) were pneumonia (17 percent), pyrexia (9 percent), sepsis (8 percent), febrile neutropenia (5 percent) and diarrhea (5 percent); SAR were reported in 49 percent of patients and 10 percent of patients discontinued due to adverse reactions.

Most common lab abnormalities (incidence ≥30 percent and ≥5 percent than rituximab alone; all grades) were neutrophils decreased, hypertriglyceridemia, hyperglycemia and ALT elevation.

Drug Interactions

CYP3A inducers: Avoid coadministration with strong CYP3A inducers.
CYP3A inhibitors: When coadministered with strong CYP3A inhibitors, monitor closely for Zydelig toxicity.
CYP3A substrates: Avoid coadministration with CYP3A substrates.

Dosage and Administration

Adult starting dose: One 150 mg tablet twice daily, swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The safe dosing regimen for patients who require treatment longer than several months is unknown.

Dose modification: Consult the Zydelig full Prescribing Information for dose modification and monitoring recommendations for the following specific toxicities: pneumonitis, ALT/AST elevations, bilirubin elevations, diarrhea, neutropenia, and thrombocytopenia. For other severe or life-threatening toxicities, withhold Zydelig until toxicity is resolved and reduce the dose to 100 mg, twice daily, upon resuming treatment. If severe or life-threatening toxicities recur upon rechallenge, Zydelig should be permanently discontinued.

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