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FDA Approves VELCADE® (bortezomib) for Injection for Previously Untreated Patients with Mantle Cell Lymphoma

On October 9, 2014 Takeda reported that the U.S. Food and Drug Administration (FDA) has approved VELCADE (bortezomib) for injection for use in previously untreated patients with mantle cell lymphoma (MCL) (Press release Takeda, OCT 9, 2014, View Source [SID:1234500832]). VELCADE is the first treatment in the United States to be approved for use in previously untreated patients with MCL. This approval extends the utility of VELCADE beyond relapsed or refractory mantle cell lymphoma, for which it has been approved since 2006.

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"Mantle cell lymphoma is a subtype of non-Hodgkin lymphoma that is usually a clinically aggressive malignancy, and it is a challenging disease to treat in part due to a relatively high risk of relapse," said Andrew Evens, DO, MSc, Director, Tufts Cancer Center; Chief, Division of Hematology/Oncology; Director, Lymphoma Program. "There are several new targeted drugs approved by the FDA for patients with relapsed or refractory disease, but up to this point, there had been none approved for the treatment of patients with previously untreated disease. VELCADE, when used in the VcR-CAP regimen, VELCADE, rituximab, cyclophosphamide, doxorubicin and prednisone, has demonstrated improved outcomes for patients, making it an important advance for the treatment of newly-diagnosed patients with mantle cell lymphoma."

This approval is based on the results of an international, randomized, head-to-head Phase 3 study that showed that previously untreated patients receiving a VELCADE-containing combination (VcR-CAP) experienced a 59 percent relative improvement in the study’s primary endpoint of progression-free survival (PFS) compared to those who were administered the standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) regimen (median 25 vs. 14 months; Hazard Ratio [HR] 0.63; P < 0.001) at a median follow up of 40 months. An Independent Review Committee (IRC) assessed the primary efficacy endpoint of PFS. The complete response (CR) rate for patients receiving VcR-CAP vs. R-CHOP was 44 percent vs. 34 percent.

"We are delighted VELCADE has received approval in previously untreated mantle cell lymphoma. The VELCADE-combination delivered an 11-month median advantage in progression-free survival as compared to a current standard of care," said Dixie-Lee Esseltine, MD, FRCPC, Vice President, Oncology Clinical Research, Takeda Pharmaceuticals International Co. "Since 2006, VELCADE has proven to be an important therapy for the treatment of relapsed or refractory mantle cell lymphoma, and it can now be used as an initial treatment for all patients with mantle cell lymphoma."

The open-label, multicenter, prospective study evaluated the efficacy and safety of VcR-CAP vs. R-CHOP in 487 patients with previously untreated MCL who were ineligible or not considered for a bone marrow transplant. VELCADE (1.3 mg/m2) is administered intravenously in combination with intravenous rituximab, cyclophosphamide, doxorubicin and oral prednisone (VcR-CAP) for six 3-week treatment cycles. VELCADE is administered first followed by rituximab. VELCADE is administered twice weekly for two weeks (days 1, 4, 8 and 11) followed by a 10‑day rest period on days 12‑21. For patients with a response first documented at cycle 6, two additional VcR-CAP cycles are recommended. At least 72 hours should elapse between consecutive doses of VELCADE.

The most common adverse reactions occurring in ≥20 percent of patients receiving the VcR-CAP regimen were neutropenia, leukopenia, anemia, thrombocytopenia, lymphopenia, peripheral neuropathy, pyrexia, nausea and diarrhea. Infections were reported for 31 percent of patients in the VcR-CAP arm and 23 percent of the patients in the R-CHOP arm including pneumonia (8 percent versus 5 percent). Adverse reactions leading to discontinuation occurred in 8 percent of patients in the VcR-CAP arm and 6 percent of patients in the R-CHOP arm. In the VcR-CAP group, the most commonly reported adverse reaction leading to discontinuation was peripheral sensory neuropathy (1 percent; 3 patients).

Cyclacel Announces Data Safety Monitoring Board Recommendation to Continue the Seamless Phase 3 Trial of Sapacitabine in AML

On October 9, 2014 Cyclacel Pharmaceuticals reported that the independent Data and Safety Monitoring Board (DSMB) for the Company’s Phase 3 SEAMLESS study in acute myeloid leukemia (AML) has completed its fourth planned safety review and recommended that the study should continue as planned without any modifications (Press release Cyclacel, OCT 9, 2014, View Source [SID:1234500809]). The DSMB reviewed available data from 317 randomized patients with at least 60 days of follow-up and noted that no safety or efficacy concerns were identified.

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"This is the fourth consecutive review for which the DSMB recommended that the SEAMLESS study should continue as planned," said Judy H. Chiao, M.D., Vice President, Clinical Development and Regulatory Affairs of Cyclacel. "We are encouraged by the DSMB’s recommendation based on their review of available data from US and European sites participating in SEAMLESS. We now have over 100 US and European sites open and expect completion of enrollment to occur in the next few months. In addition to SEAMLESS, we are conducting feasibility assessment of our Phase 2b randomized study of sapacitabine in older patients with myelodysplastic syndromes (MDS) after treatment failure of hypomethylating agents."

SEAMLESS is a Phase 3, randomized, registration-directed study of oral sapacitabine capsules in elderly (70 years or older) patients with AML who are unfit for or have refused intensive chemotherapy. The primary endpoint is overall survival. SEAMLESS is being conducted under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA). The DSMB will perform an interim analysis for futility once half of the required events have been observed.

CytRx Initiates Phase 1b Clinical Trial with Combination of Aldoxorubicin and Gemcitabine in Patients with Metastatic Solid Tumors

On October 9, 2014 CytRx Corporation reported the initiation of enrollment in an open-label Phase 1b clinical trial designed to investigate the preliminary safety and activity of aldoxorubicin plus gemcitabine in subjects with metastatic solid tumors (Press release CytRx, OCT 9, 2014, View Source [SID:1234500810]). Aldoxorubicin is CytRx’s modified version of the widely-used chemotherapeutic agent, doxorubicin.

The Phase 1b clinical trial will be conducted at the Virginia G. Piper Cancer Center in Scottsdale, AZ, the Samuel Oschin Cancer Center at Cedars Sinai Medical Center, Los Angeles, CA, and the Sarcoma Oncology Center in Santa Monica, CA. The clinical trial is expected to enroll up to 30 male and female patients between the ages of 15 and 80 with advanced, unresectable, metastatic solid tumors that have either relapsed or were refractory to treatment with at least one prior chemotherapy or immunotherapy regimen and for which no standard approved therapy exists. The Company expects to complete enrollment by the third quarter of 2015.

“Initiation of clinical development of aldoxorubicin in combination with gemcitabine for the treatment of metastatic solid tumors represents a potentially significant expansion of our aldoxorubicin franchise in cancer treatment,” said CytRx CEO Steven A. Kriegsman. “The start of this combination chemotherapy with aldoxorubicin will allow our testing to move into a variety of new tumors such as pancreatic and ovarian cancers as well as hematological malignancies.”

For this clinical trial, aldoxorubicin will be administered at escalating doses by intravenous infusion (IVI) on Day 1 every 21 days plus 900 mg/m2 gemcitabine on Days 1 and 8 every 21 days until disease progression, unacceptable toxicity or the patient withdraws consent. The primary objective of the trial is to determine the preliminary safety of administration of aldoxorubicin in combination with gemcitabine in subjects with metastatic solid tumors as measured by the frequency and severity of adverse events (AEs), abnormal findings on physical examination, laboratory tests, vital signs, echocardiograms (ECHO) or multiple-gated acquisition (MUGA) scans, electrocardiogram (ECG) results, and weight. The secondary objective of the trial is to evaluate the activity of aldoxorubicin in combination with gemcitabine in this population, assessed by overall response rate (ORR), progression-free survival (PFS), and PFS at 4 and 6 months.

Aldoxorubicin is also currently being studied in a pivotal global Phase 3 clinical trial evaluating the efficacy and safety of aldoxorubicin as a second-line treatment for patients with STS under a Special Protocol Assessment with the FDA. CytRx is also evaluating aldoxorubicin in two Phase 2 clinical trials, one in patients with late-stage glioblastoma (GBM) and the other in HIV-related Kaposi’s sarcoma, a global Phase 2b clinical trial in patients with relapsed small cell lung cancer, and in a Phase 1b trial in combination with ifosfamide in patients with soft tissue sarcoma.

Amgen’s BiTE Immunotherapy Blinatumomab Receives FDA Priority Review Designation In Acute Lymphoblastic Leukemia

On October 9, 2014 Amgen reported that the U.S. Food and Drug Administration (FDA) has accepted for review the Biologics License Application (BLA) for the investigational bispecific T cell engager (BiTE) antibody construct, blinatumomab (Press release Amgen, OCT 9, 2014, View Source [SID:1234500807]). The BLA is for the treatment of adults with Philadelphia-negative (Ph-) relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL), a rapidly progressing cancer of the blood and bone marrow. As part of the acceptance, the FDA granted blinatumomab priority review with a Prescription Drug User Fee Act (PDUFA) action date of May 19, 2015.

A Marketing Authorization Application (MAA) has also been submitted to the European Medicines Agency (EMA) via the centralized procedure for approval to market blinatumomab for the treatment of adults with Ph- relapsed/refractory B-precursor ALL.

The submissions include data from a Phase 2 trial of adult patients with Ph- relapsed/refractory B-precursor ALL treated with blinatumomab, which met its primary endpoint.

“The FDA’s acceptance of our BLA submission and designation of priority review for blinatumomab underscores the need to provide new treatment approaches for adult patients with relapsed or refractory ALL, and we are encouraged by the Agency’s expedited review,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “Blinatumomab has the potential to make a significant impact for these patients, and this milestone, along with other ongoing filings around the world, represents the potential of BiTE technology in cancers that are challenging to treat.”

BiTE antibody constructs represent an innovative immunotherapy approach that helps the body’s immune system target cancer cells. Blinatumomab, the first of the investigational BiTE antibody constructs, has received orphan drug designation from the EMA and FDA, and breakthrough therapy and priority review designation from the FDA for the treatment of ALL.

According to the FDA, priority review designation is assigned to applications for drugs that treat serious conditions and would, if approved, provide significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions. A priority review designation will set a goal date for taking action on an application within six months of receipt.

In the U.S., more than 6,000 cases of ALL will be diagnosed in 2014, and in the European Union, it is estimated that more than 7,000 cases of ALL are diagnosed each year. In adult patients with relapsed or refractory ALL, median overall survival is just three to five months.

8-K – Current report

On October 7, 2014 Bio-Path Holdings reported that it has successfully completed Cohort 6 of its Phase I clinical trial evaluating lead compound, Liposomal Grb-2, in blood cancers (Filing 8-K , Bio-Path Holdings, OCT 8, 2014, View Source [SID:1234500808]). Bio-Path now plans to move the compound into Phase II clinical trials.

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Three patients were evaluated in Cohort 6 of the Phase I clinical trial and this cohort was consistent with previous cohorts in demonstrating that Liposomal Grb-2 is safe and well tolerated with the drug showing signs of anti-leukemia activity. As a result of the safety profile of the drug, a maximum tolerated dose has yet to be reached.

A total of 34 patients, of which 21 were evaluable, enrolled into the Phase I clinical trial, which evaluated escalating doses of Liposomal Grb-2 (5, 10, 20, 40, 60 and 90 mg/m2 ). Patients were treated twice a week for four weeks, for a total of eight doses.

Bio-Path is now completing an analysis of the Phase I data to submit to the U.S. Food and Drug Administration (FDA). It expects to begin its Phase II program by the end of 2014. It is anticipated that the first of three Phase II clinical trials will evaluate Liposomal Grb-2 as a combination therapy in Acute Myeloid Leukemia (AML).

"The completion of Cohort 6 is a significant milestone for Bio-Path and moves the Company into its next phase of development with its novel liposomal delivery technology," said Peter Nielsen, President and Chief Executive Officer of Bio-Path. "We will now move this program into Phase II while also extending the Phase I portion to continue testing higher doses since we have not yet reached a maximum tolerated dose."