On January 20, 2018 Array BioPharma Inc. (Nasdaq: ARRY) and Pierre Fabre reported updated results from the 30 patient safety lead-in of the Phase 3 BEACON CRC trial evaluating the triplet combination of encorafenib, a BRAF inhibitor, binimetinib, a MEK inhibitor and cetuximab, an anti-EGFR antibody, in patients with BRAF-mutant metastatic colorectal cancer (CRC) whose disease has progressed after one or two prior regimens (Press release, Array BioPharma, JAN 20, 2018, View Source;p=RssLanding&cat=news&id=2327568 [SID1234523363]). The data were presented at the ASCO (Free ASCO Whitepaper) 2018 Gastrointestinal Cancers Symposium in San Francisco, California.

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!

In patients with the BRAFV600E mutation, the estimated median progression-free survival (mPFS) at the time of analysis was 8 months. The confirmed overall response rate (ORR)* in patients with the BRAFV600E mutation was 48%, and 3 patients achieved complete responses (CR). Further, the ORR was 62% in the 16 patients (10/16) who received only one prior line of therapy. These data represent substantial improvements compared to several separate historical published standard of care benchmarks for this population.

"We are very excited about these safety lead-in results, which show both an unprecedented progression-free survival and overall response rate in patients with BRAFV600-mutant colorectal cancer," said Scott Kopetz, M.D., Ph.D., FACP, Associate Professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. "To put these data in context, the observed median progression-free survival of 8 months exceeds historical benchmarks of approximately 2 months for median progression-free survival, and 4 to 6 months for median overall survival, with current standards of care in this patient population. These results demonstrate the potential of the triplet combination to benefit this population of patients who currently have very limited effective treatment options."

In the safety lead-in, the triplet combination was generally well-tolerated. Two patients discontinued treatment due to adverse events (AEs) with only one of these considered related to treatment. The most common grade 3 or 4 AEs seen in at least 10% of patients were fatigue (4/30), urinary tract infection (3/30), increased aspartate aminotransferase (AST; 3/30) and increased blood creatine kinase (CK; 3/30).

All patients with elevated baseline levels of the tumor markers CEA and CA19-9 had a reduction from baseline, with similar and substantial (median 83% – 96%) reductions across both markers in patients with objective responses and those with stable disease.

The enrollment in the randomized portion of the BEACON CRC trial is ongoing. Patients interested in participating in this trial may talk to their doctor to have their tumor tested for the BRAF mutation for eligibility to enroll in this new and important trial. Further details on the trial are available at clinicaltrials.gov (NCT02928224).

A PDF of the ASCO (Free ASCO Whitepaper) 2018 Gastrointestinal Cancers Symposium presentation can be found on Array’s website: View Source

*Overall response rate (ORR) = Complete response (CR) + Partial response (PR)

About BEACON CRC
BEACON CRC is a randomized, open-label, global trial evaluating the efficacy and safety of encorafenib, binimetinib and cetuximab in patients with BRAF-mutant metastatic CRC whose disease has progressed after one or two prior regimens. Thirty patients were treated in the safety lead-in and received the triplet combination (encorafenib 300 mg daily, binimetinib 45 mg twice daily and cetuximab per label). Of the 30 patients, 29 had a BRAFV600E mutation. Microsatellite instability-high (MSI-H), resulting from defective DNA mismatch repair, was detected in only 1 patient. As previously announced, the triplet combination demonstrated good tolerability, supporting initiation of the randomized portion of the trial.

The randomized portion of the BEACON CRC trial is designed to assess the efficacy of encorafenib in combination with cetuximab with or without binimetinib compared to cetuximab and irinotecan-based therapy. Approximately 615 patients are expected to be randomized 1:1:1 to receive triplet combination, doublet combination (encorafenib and cetuximab) or the control arm (irinotecan-based therapy and cetuximab). The primary endpoint of the trial is overall survival of the triplet combination compared to the control arm. Secondary endpoints address efficacy of the doublet combination compared to the control arm, and the triplet combination compared to the doublet therapy. Other secondary endpoints include PFS, ORR, duration of response, safety and tolerability. Health related quality of life data will also be assessed. The trial will be conducted at over 250 investigational sites in North America, South America, Europe and the Asia Pacific region. Patient enrollment is expected to be completed in 2018.

BEACON CRC is the first and only Phase 3 trial designed to test a BRAF/MEK combo targeted therapy in BRAF-mutant advanced CRC. Phase 2 trial results were presented at the 2016 ASCO (Free ASCO Whitepaper) annual meeting. [1] In the doublet arm of encorafenib and cetuximab, median overall survival (mOS) exceeded one year, which is more than double several separate historical published standard of care benchmarks for this population. [1-7] Further, the ORR was 22% and the mPFS was 4.2 months. [1] Historical published ORR and mPFS benchmarks in this patient population using standard of care regimens range between 4% to 8% and 1.8 and 2.5 months, respectively. [5-8]

About Colorectal Cancer
Worldwide, colorectal cancer is the third most common type of cancer in men and the second most common in women, with approximately 1.4 million new diagnoses in 2012. Of these, nearly 750,000 were diagnosed in men, and 614,000 in women. Globally in 2012, approximately 694,000 deaths were attributed to colorectal cancer. In the U.S. alone, an estimated 140,250 patients will be diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 are estimated to die of their disease. [9] In the U.S., BRAF mutations are estimated to occur in 10% to 15% of patients with colorectal cancer and represent a poor prognosis for these patients. [3, 4, 10, 11] Based on recent prospective historical data, the prevalence of MSI-H in tumors from patients with metastatic BRAF-mutant CRC ranged from 14% in a recent Phase 1b/2 trial (NCT01719380) (Array, data on file) to 18% in a recent Southwestern Oncology Group (SWOG) randomized phase 2 trial. [7]

About Encorafenib and Binimetinib
BRAF and MEK are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma and colorectal cancer. Encorafenib is a late-stage small molecule BRAF inhibitor and binimetinib is a late-stage small molecule MEK inhibitor, both of which target key enzymes in this pathway. Encorafenib and binimetinib are being studied in clinical trials in advanced cancer patients, including the Phase 3 BEACON CRC trial and the Phase 3 COLUMBUS trial.

The U.S. Food and Drug Administration (FDA) is currently reviewing the New Drug Applications (NDAs) to support use of the combination of encorafenib and binimetinib for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma. The FDA set a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2018 for both applications. In addition, the European Medicines Agency (EMA) is reviewing the Marketing Authorization Applications for encorafenib and binimetinib.

Encorafenib and binimetinib are investigational medicines and are not currently approved in any country.

Array BioPharma has exclusive rights to encorafenib and binimetinib in the U.S. and Canada. Array has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America. The BEACON CRC trial is being conducted with support from Pierre Fabre and Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

On January 19, 2018 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that it has entered into a licensing agreement granting exclusive rights concerning the research, development, manufacture and marketing of Eisai’s in-house discovered potential anticancer agent E7046, which is an investigational prostaglandin E2 (PGE2) type EP4 receptor antagonist, to Adlai Nortye Biopharma Co., Ltd. (Headquarters: Hangzhou, China, "Adlai Nortye") in all regions outside of Japan and part of Asia (excluding China) (Press release, Eisai, JAN 19, 2018, View Source [SID1234553913]).

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!

E7046 is an orally administered, selective EP4 receptor antagonist discovered by Eisai’s U.S. Andover research facility. It is suggested that PGE2 signals through EP4 receptors may suppress the antitumor activity of immune cells. By inhibiting EP4, E7046 is expected to act on the tumor microenvironment via a different mechanism to immune checkpoint inhibitors to potentially demonstrate antitumor effects. Currently, E7046 is being investigated as a monotherapy in a Phase I clinical study as well as a Phase Ib clinical study in combination with radiotherapy/chemoradiotherapy.

Under this agreement, Eisai will receive from Adlai Nortye a one-time payment, milestone payments in accordance with the progress of development, as well as certain royalties according to sales revenue after launch.

Adlai Nortye is a science-led clinical stage biopharmaceutical company dedicated to discovering, developing and commercializing new and effective immunotherapy for patients with cancer. Eisai positions oncology as a key therapeutic area, and is aiming to discover revolutionary new medicines with the potential to cure cancer. By licensing E7046 to Adlai Nortye, which is developing several tumor immunotherapies that have synergies with E7046, Eisai aims to maximize the value of the agent in order to hopefully contribute to the treatment of patients in the future who need tumor immunotherapies as soon as possible.

On January 19, 2018 AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that the Japanese Ministry of Health, Labour and Welfare has approved LYNPARZA (olaparib) tablets (300mg twice daily) for use as a maintenance therapy for patients with platinum-sensitive relapsed ovarian cancer, regardless of their BRCA mutation status, who responded to their last platinum-based chemotherapy. LYNPARZA is the first poly ADP-ribose polymerase (PARP) inhibitor to be approved in Japan (Press release, Merck & Co, JAN 19, 2018, View Source [SID1234523308]).

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!

Dave Fredrickson, executive vice president, head of the oncology business unit at AstraZeneca, said, "We are proud to bring this important first-in-class treatment to women with platinum-sensitive relapsed ovarian cancer in Japan who currently have very few treatment options. The trials show that with LYNPARZA maintenance therapy, women with ovarian cancer can live longer without their disease worsening and LYNPARZA is well tolerated."

Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, "Today’s decision is significant for LYNPARZA and, more importantly, for Japanese patients living with advanced ovarian cancer. Our global collaboration with AstraZeneca further reinforces how our joint efforts can advance science for patients and we look forward to working together to explore the potential of LYNPARZA across multiple tumor types."

The approval was granted on the basis of two randomized trials of LYNPARZA (olaparib) maintenance therapy for platinum-sensitive relapsed ovarian cancer, SOLO-2 and Study 19.

Table 1. Summary of key efficacy results from randomized trials:

Analysis
Reduction in the risk of
disease progression or death
(PFS)

Reduction in the risk of
death (OS)

SOLO-2
[gBRCAm]

n=295

LYNPARZA
70% (HR 0.30 [95% CI, 0.22-
0.41], P<0.0001; median 19.1
vs 5.5 months by investigator-
assessed analysis)

Data not yet mature
Placebo
Study 19
[PSR OC*]

n=265

LYNPARZA
65% (HR 0.35 [95% CI, 0.25-
0.49], P<0.0001; median 8.4
vs 4.8 months)

27% (HR 0.73 [95% CI,
0.55-0.95]; median 29.8 vs
27.8 months)

Placebo
*PSR = Platinum-sensitive recurrent ovarian cancer

In SOLO-2, the most common adverse drug reactions (≥20%) of any grade reported in patients in the LYNPARZA arm were nausea (66.7%), anemia (39.0%), fatigue (29.7%), vomiting (25.6%), asthenia (24.1%) and dysgeusia (23.1%).

In Study 19, the most common adverse drug reactions (≥20%) of any grade reported in patients in the LYNPARZA arm were nausea (64.0%), fatigue (43.4%) and vomiting (21.3%).

LYNPARZA is also currently under review for use in unresectable or recurrent BRCA-mutated HER2-negative breast cancer in Japan, with a decision expected in the second half of 2018 based upon a priority review.

About Ovarian Cancer in Japan

Worldwide, ovarian cancer is the seventh most-commonly diagnosed cancer and the eighth most-common cause of cancer deaths in women. In Japan, more than 9,000 women are diagnosed with ovarian cancer every year and the five-year survival rate is 58 percent, the lowest among all gynecological cancers. In 2012, 4,758 women with ovarian cancer died, which represents one out of every two patients. As there is no cure for relapsed ovarian cancer, the primary aim of treatment is to slow progression of the disease for as long as possible and improving or maintaining a patient’s quality of life.

Indications for LYNPARZA (olaparib) in the U.S.

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

In patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Important Safety Information for LYNPARZA (olaparib)

Contraindications

There are no contraindications for LYNPARZA.

Warnings and Precautions

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA (olaparib) if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose. Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

Adverse Reactions—Maintenance Setting

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA (olaparib) in the maintenance setting for SOLO-2: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).

Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), and decreased appetite (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

Adverse Reactions—Advanced gBRCAm Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA (olaparib) for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue (including asthenia) (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), increase in mean corpuscular volume (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

Adverse Reactions—gBRCAm, HER2-Negative Breast Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

Drug Interactions

Anticancer Agents: Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA (olaparib). If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of LYNPARZA.

Use In Specific Populations

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild hepatic impairment (Child-Pugh classification A). There are no data in patients with moderate or severe hepatic impairment.

Renal Impairment: No adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51-80 mL/min). In patients with moderate renal impairment (CLcr=31-50 mL/min), reduce the dose to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

Dosing and Administration

To avoid substitution errors and overdose, do not substitute LYNPARZA (olaparib) tablets with LYNPARZA capsules on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation. Recommended tablet dose is 300 mg, taken orally twice daily, with or without food. Continue treatment until disease progression or unacceptable toxicity. For adverse reactions, consider dose interruption or dose reduction.

NOTES TO EDITORS

About SOLO-2

SOLO-2 was a phase 3, randomized, double-blinded, multicenter trial designed to determine the efficacy of LYNPARZA tablets as a maintenance monotherapy compared with placebo, in patients with platinum-sensitive, relapsed or recurrent gBRCA-mutated ovarian, fallopian tube and primary peritoneal cancer. The trial, conducted in collaboration with the European Network for Gynaecological Oncological Trial Groups (ENGOT) and Groupe d’Investigateurs National pour l’Etude des Cancers de l’Ovaire et du sein (GINECO), randomized 295 patients with documented germline BRCA1 or BRCA2 mutations who had received at least two prior lines of platinum-based chemotherapy and were in complete or partial response. Eligible patients were randomized to receive 300mg LYNPARZA (olaparib) tablets twice daily or placebo tablets twice daily.

About Study 19

Study 19 was a phase II, randomized, double-blinded, placebo-controlled, multicenter trial, which evaluated the efficacy and safety of LYNPARZA compared with placebo in relapsed, high-grade serous ovarian cancer patients. The trial randomized 265 patients regardless of BRCA mutation status and who had completed at least two courses of platinum-based chemotherapy and their most recent treatment regimen. Eligible patients were randomized to receive LYNPARZA maintenance monotherapy at a dose of 400mg per day or matching placebo.

About LYNPARZA (olaparib)

LYNPARZA is a first-in-class poly ADP-ribose polymerase (PARP) inhibitor and the first targeted treatment to potentially exploit tumor DNA damage response (DDR)-pathway deficiencies to preferentially kill cancer cells. Specifically, in vitro studies have shown that LYNPARZA-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

LYNPARZA is being investigated in a range of DDR-deficient tumor types.

On January 19, 2018 Celgene Corporation (NASDAQ: CELG) reported primary endpoint findings and updated results of secondary endpoints from the phase II international LAPACT trial of ABRAXANE (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) plus gemcitabine in patients with locally advanced pancreatic cancer (Press release, Celgene, JAN 19, 2018, View Source [SID1234523366]). The results were presented today at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO GI) in San Francisco, California.

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!

An analysis of patients with newly diagnosed, locally advanced pancreatic cancer treated with up to 6 cycles of ABRAXANE + gemcitabine as an investigational induction therapy (n=106) found that patients had a median time to treatment failure (TTF) of 8.8 months (90% CI: 6.67-9.82), which exceeded the protocol-specified target of 6.6 months (primary endpoint). Secondary endpoints included evaluation of the disease control rate (DCR), overall response rate (ORR), progression free survival (PFS) and overall survival (OS) in patients treated with an ABRAXANE + gemcitabine induction therapy. The updated analysis found a 77.6% DCR ≥ 16 wks (DCR ≥ 16 wks: stable disease (SD) ≥ 16 wks = 44.9%, CR = 0%, PR = 32%) and 65.4% DCR ≥ 24 wks (DCR ≥ 24 wks: SD ≥ 24 wks = 32.7%, CR = 0%, PR = 32%). The ORR was 32% (CR=0%, PR=32%), the median PFS was 10.8 months (9,26-11.63; 90% CI) and 12-month estimated OS was 72% (64.5% – 78.9%; 90% CI). One or more treatment emergent adverse event occurred in 99% of patients during induction. The most common Grade ≥ 3 adverse events (AE) (≥10%) were neutropenia (42%), anemia (11%), and fatigue (10%).

"Pancreatic cancer remains an extremely challenging disease to treat because it is often diagnosed at the metastatic stage, and even those diagnosed with locally advanced disease typically have a poor prognosis," said Dr. Pascal Hammel, Gastroenterologist/Oncologist, Hôpital Beaujon, Clichy France. "Disease control is key in our patients with locally advanced disease, as it may lead to opportunities for additional treatment interventions, including radiotherapy, or even, in some favorable cases, surgical resection. The results from this study are encouraging, as it shows that induction therapy has the potential to help us achieve disease control in these locally advanced patients."

In this prospective, phase II trial conducted in the US, Canada and Europe, patients with protocol-defined locally advanced, unresectable pancreatic cancer received an induction regimen of up to 6 cycles of ABRAXANE + gemcitabine, followed by the investigator’s choice (IC) of either (a) continuation of the ABRAXANE + gemcitabine regimen, (b) treatment with chemoradiation, or (c) surgery. More than half of patients (57.5%, n = 61/106) completed the induction phase with ABRAXANE + gemcitabine treatment. Forty two percent (45/106) of patients did not complete induction treatment and the reasons for treatment discontinuation during induction included adverse events (n = 20), progressive disease (n = 8), protocol non-compliance (n = 5), physician decision (n = 6), death (n = 2), and other reasons (n = 4). At the time of data cut-off, 45 patients in the intent to treat cohort received IC therapy after induction: 11% (12/106) of patients continued ABRAXANE + gemcitabine per the protocol; 16% (17/106) received chemoradiation; and 15% of patients (16/106) with unresectable disease at the start of the study underwent tumor resection surgery following ABRAXANE + gemcitabine induction therapy. The LAPACT presentation also reported patient-reported quality of life findings across twenty-nine different symptom measures using the EORTC QLQ-C30 questionnaires.

Other relevant grade ≥3 TEAEs included thrombocytopenia (7.5%), peripheral sensory neuropathy (3.8%), diarrhea (3.8%), and febrile neutropenia (3.8%). AEs of any grade included: neutropenia (58.5%), fatigue (50%), anemia (47.2%), diarrhea (46.2%), thrombocytopenia (41.5%), peripheral sensory neuropathy (23.6%), and febrile neutropenia (3.8%).

"Since its approval to treat metastatic pancreatic cancer in 2013, the ABRAXANE + gemcitabine regimen has become a standard of care in first-line metastatic pancreatic cancer," said Nadim Ahmed, President, Hematology and Oncology for Celgene. "The findings from LAPACT offer insight into the potential of ABRAXANE-based treatment for locally advanced pancreatic cancer patients and it’s encouraging to see a nearly 9-month time to treatment failure in these patients treated with an ABRAXANE regimen."

ABRAXANE is not indicated for the first-line treatment of locally advanced pancreatic cancer.

ABOUT LAPACT,

LAPACT is an international, non-randomized, open-label, multi-center, phase II clinical trial conducted at 42 centers in 5 countries. The study evaluated the safety and efficacy of the investigational use of ABRAXANE in combination with gemcitabine as a first-line treatment of patients with locally advanced pancreatic cancer who were not eligible for resection surgery at trial initiation.

The trial evaluated 106 patients with locally advanced pancreatic cancer who had not received prior treatment for their pancreatic cancer and were classified as unresectable at the start of the trial. Patients were given ABRAXANE 125 mg/m2 followed by gemcitabine 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle for up to six cycles. Patients completing six cycles of treatment were given subsequent investigator-determined treatment of either: continuation of the ABRAXANE + gemcitabine regimen; chemoradiation therapy with capecitabine or gemcitabine + radiation; or surgical intervention. The median age of the patients was 65 years.

Currently, there are more than 130 studies evaluating the use of ABRAXANE in patients with pancreatic cancer in combination with more than 50 novel agents.

ABOUT ABRAXANE

ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

Important Safety Information

WARNING – NEUTROPENIA

Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE
Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS
CONTRAINDICATIONS

Neutrophil Counts

ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1500 cells/mm3
Hypersensitivity

Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug
WARNINGS AND PRECAUTIONS

Hematologic Effects

Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 47% of patients with non-small cell lung cancer (NSCLC) and 38% of patients with pancreatic cancer
Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 for NSCLC and for pancreatic cancer
Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3
In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended
Nervous System

Sensory neuropathy is dose- and schedule-dependent
The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification
If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE
Sepsis

Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine
Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis
If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics
For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels
Pneumonitis

Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine
Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis
Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis
Hypersensitivity

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported
Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug
Hepatic Impairment

Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution
Patients with hepatic impairment may be at an increased risk of toxicity, particularly from myelosuppression, and should be monitored for development of profound myelosuppression
For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and AST ≤10 x ULN)
Albumin (Human)

ABRAXANE contains albumin (human), a derivative of human blood
Use in Pregnancy: Pregnancy Category D

ABRAXANE can cause fetal harm when administered to a pregnant woman
If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus
Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE
Use in Men

Men should be advised not to father a child while receiving ABRAXANE
ADVERSE REACTIONS

Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)
Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)
Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group
The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)
The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%)
The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)
The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)
Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%)
Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)
Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations

Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied
There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs
There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration
DRUG INTERACTIONS

Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4
USE IN SPECIFIC POPULATIONS

Nursing Mothers

It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
Pediatric

The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated
Geriatric

Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC
Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas
Renal Impairment

There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance < 30 mL/min)
DOSAGE AND ADMINISTRATION

Do not administer ABRAXANE to any patient with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN
Do not administer ABRAXANE to patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment
Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity
Monitor patients closely
Please see full Prescribing Information, including Boxed WARNING.

On January 19, 2018 TRACON Pharmaceuticals (NASDAQ:TCON), a clinical stage biopharmaceutical company focused on the development and commercialization of novel targeted therapeutics for cancer, wet age-related macular degeneration and fibrotic diseases, reported that positive initial clinical data from its ongoing Phase 1b/2 study of TRC105 and Nexavar (sorafenib) in patients with advanced hepatocellular carcinoma (HCC) were presented in a poster presentation at the 2018 ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium in San Francisco, California (Press release, Tracon Pharmaceuticals, JAN 19, 2018, View Source;p=RssLanding&cat=news&id=2327502 [SID1234523376]).

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!

Initial data from the ongoing open-label, non-randomized study were presented by Dr. Kanwal Raghav from the University of Texas MD Anderson Cancer Center:

Partial responses by RECIST 1.1 occurred in 2 of 8 (25%) evaluable patients and a reduction of 50% or greater in alpha fetoprotein (AFP) concentration occurred in 3 of 8 (38%) evaluable patients. Reduction in AFP, a tumor marker expressed in patients with HCC, in early treatment may help identify a favorable response to treatment and was observed in both cases of partial response.
Hybrid dosing consisting of four weekly doses of TRC105 at 10 mg/kg followed by every other week dosing at 15 mg/kg thereafter was tolerable when given with the standard Nexavar dose of 400 mg twice daily.
Adverse events typical of each drug did not increase in frequency or severity when the drugs were administered concurrently.
The trial is ongoing, with the completion of the enrollment of approximately 33 patients expected by the end of 2018.
"We continue to be encouraged with the safety and activity of TRC105 in combination with Nexavar in patients with HCC, a tumor type with limited treatment options," said Charles Theuer, M.D., Ph.D., President and CEO of TRACON. "Importantly, the initial data from the current trial are consistent with the 33% partial response rate by RECIST 1.1 reported in the completed Phase 1/2 study published by the National Cancer Institute in 2017. We expect to complete enrollment of the current multicenter study by the end of 2018, and will discuss a potential registration-enabling study of the combination of TRC105 and Nexavar in HCC with regulatory authorities shortly thereafter."

The poster is available on TRACON’s website at: www.traconpharma.com/publications.php

About Carotuximab (TRC105)

TRC105 is a novel, clinical stage antibody to endoglin, a protein overexpressed on proliferating endothelial cells that is essential for angiogenesis, the process of new blood vessel formation. TRC105 is currently being studied in a pivotal Phase 3 trial in angiosarcoma and multiple Phase 2 clinical trials, in combination with VEGF inhibitors. TRC105 has received orphan designation for the treatment of soft tissue sarcoma in both the U.S. and EU. The ophthalmic formulation of TRC105, DE-122, is currently in a randomized Phase 2 trial for patients with wet AMD. For more information about the clinical trials, please visit TRACON’s website at www.traconpharma.com/clinical_trials.php.