On April 6, 2015 Celldex Therapeutics reported the initiation of a Phase 1/2 safety pilot and expansion study examining the investigational combination of varlilumab and ipilimumab (Yervoy; Bristol-Myers Squibb) in patients with Stage III or IV metastatic melanoma (Press release, Celldex Therapeutics, APR 6, 2015, View Source [SID:1234502931]). Varlilumab is Celldex’s fully human monoclonal antibody that targets CD27, a critical co-stimulatory molecule in the immune activation cascade. Ipilimumab, a recombinant, human monoclonal antibody that blocks CTLA-4, is FDA approved for the treatment of unresectable or metastatic melanoma. In the Phase 2 portion of the study, patients with tumors that express NY-ESO-1 will also receive CDX-1401, Celldex’s off-the-shelf antibody-based dendritic cell vaccine that targets tumors expressing the NY-ESO-1 oncoprotein.

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The three agents in this study were specifically selected because they uniquely intervene at key points of immune regulation and because Celldex has observed enhanced activity in preclinical studies when varlilumab is combined with either checkpoint inhibitors or with vaccines. In addition, this study will also build on previous clinical data from the CDX-1401 experience that suggests that CDX-1401 may predispose patients to better outcome on checkpoint inhibitors, including ipilimumab.

"We believe sophisticated combination approaches centered on immunotherapy hold significant promise for the treatment of cancer and, to this end, are committed to exploring novel combinations across a broad array of mechanisms and indications. This latest trial marks the third Phase 1/2 combination study that varlilumab has entered and the first three-drug combination study," said Thomas Davis, MD, Executive Vice President and Chief Medical Officer of Celldex Therapeutics.

The Phase 1 portion of the study will assess the safety and tolerability of varlilumab at 0.3 and 3.0 mg/kg in combination with ipilimumab at 3 mg/kg administered every three weeks to identify a recommended dose for the Phase 2 portion of the study. The Phase 2 study will include two cohorts—one comprised of patients who are NY-ESO-1 positive and one comprised of patients who are NY-ESO-1 negative. Patients who are NY-ESO-1 positive will also receive CDX-1401 dosed at 1 mg (with poly-ICLC at 2 mg given as an adjuvant) every three weeks in addition to varlilumab and ipilimumab. In total, up to four doses of study treatment will be administered. The primary objective for both cohorts is objective response rate up to 24 weeks (ORR6) using standard, modified World Health Organization response criteria. Secondary objectives for the Phase 2 study include safety and tolerability, immunogenicity, pharmacokinetics and further assessment of anti-tumor activity across a broad range of endpoints.

About Varlilumab

Varlilumab is a fully human monoclonal antibody that targets CD27, a critical molecule in the activation pathway of lymphocytes. CD27 can be effectively manipulated with activating antibodies to induce potent anti-tumor responses and may result in fewer toxicities due to its restricted expression and regulation. Varlilumab is a potent anti-CD27 agonist that induces activation and proliferation of human T cells when combined with T cell receptor stimulation. In lymphoid malignancies that express CD27 at high levels, varlilumab may have an additional mechanism of action through a direct anti-tumor effect. Varlilumab has completed a Phase 1 dose-escalation study, demonstrating potent immunologic activity consistent with its mechanism of action and anti-tumor activity in patients with advanced, refractory disease. No maximum tolerated dose was reached and minimal toxicities were observed. Celldex has initiated a broad development program for varlilumab to explore its role as an immune activator in combination with a number of complementary investigational and approved oncology drugs. Varlilumab is currently being studied in three Phase 1/2 combination studies and several additional combination studies will be initiated in 2015.

About CDX-1401

CDX-1401 is a next-generation, off-the-shelf cancer vaccine designed to activate the patient’s immune system against cancers that express the tumor marker, NY-ESO-1. CDX-1401 consists of a fully human monoclonal antibody with specificity for the dendritic cell receptor DEC-205 genetically linked to the NY-ESO-1 tumor antigen. Celldex has accessed NY-ESO-1 through a licensing agreement with the Ludwig Institute for Cancer Research. By selectively delivering the NY-ESO-1 antigen to dendritic cells in the body, CDX-1401 is intended to induce robust immune responses against the antigen-expressing cancer cells.

On April 6, 2015 ARIAD Pharmaceuticals reported that Health Canada has approved the use of Iclusig (as ponatinib hydrochloride) in Canada for the treatment of adult patients with all phases of chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom other tyrosine kinase inhibitor (TKI) therapy is not appropriate, including CML or Ph+ ALL that is T315I mutation positive, or where there is prior TKI resistance or intolerance (Press release, Ariad, APR 6, 2015, View Source [SID:1234502927]).

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"Patients with CML or Ph+ ALL can become resistant to their therapies over time," said Professor Jeffrey Lipton, Ph.D., M.D., staff physician at The Princess Margaret Cancer Centre and one of the PACE trial investigators. "Iclusig will be a valuable new therapeutic option in Canada for patients with refractory CML and Ph+ ALL, where we have a proven unmet medical need."

Iclusig is approved under the Notice of Compliance with Conditions (NOC/c) policy based on promising evidence of clinical effectiveness following review by Health Canada. Products approved under this policy are intended for the treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating illness, and have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment. In addition, these products either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies.

"Throughout the development of Iclusig, we have worked closely with leading academic centers and clinical investigators in Canada. Iclusig is the only TKI that has been approved in Canada for indications that include CML and Ph+ ALL patients with the T315I mutation," stated Harvey J. Berger, M.D., chairman and chief executive officer of ARIAD. "We will strive to make Iclusig available as quickly as possible to appropriate patients with Ph+ leukemias throughout Canada."

Iclusig will be made available through a controlled distribution program. Under this program, prescribers who have completed the certification procedure are able to prescribe Iclusig. Trained pharmacies will verify the prescriber’s certified status prior to dispensing Iclusig to the patient.

"Iclusig provides a new treatment option for patients with difficult-to-treat CML or Ph+ ALL who previously had limited therapies available to them," said Cheryl-Anne Simoneau, president and chief executive officer at the Chronic Myelogenous Leukemia Society of Canada. "For appropriate patients, this can be an important new treatment option."

The Health Canada decision was based on two-year data from the pivotal Phase 2 PACE trial in patients with CML or Ph+ ALL who were resistant or intolerant to prior TKI therapy, or who had the T315I mutation of BCR-ABL. Iclusig demonstrated anti-leukemic activity, achieving a major cytogenetic response (MCyR) in 56 percent of chronic-phase CML patients and in 70 percent of patients with the T315I mutation. MCyR within the first 12 months of treatment was the primary endpoint of the PACE trial for chronic-phase patients.

In patients with advanced disease, 57 percent of accelerated-phase CML patients and 31 percent of blast-phase CML patients achieved a major hematologic response (MaHR) with Iclusig. MaHR within the first 6 months was the primary endpoint in the trial for patients with advanced disease. In patients with Ph+ ALL, 41 percent achieved MaHR.

ARIAD’s upcoming dose-ranging trial to evaluate three starting doses of Iclusig in patients with refractory, chronic-phase CML who are resistant to at least two approved TKIs — planned to begin in mid-2015 — will serve as the confirmatory trial for the Health Canada approval.

About CML and Ph+ ALL

CML is a cancer of the white blood cells that according to the Chronic Myelogenous Leukemia Society of Canada affects 1 in 100,000, with about 5,500 Canadians living with the disease. In 2010, more than 550 people in Canada were expected to be diagnosed with CML, and 480 people were expected to be diagnosed with ALL.

CML is characterized by an excessive and unregulated production of white blood cells by the bone marrow due to a genetic abnormality that produces the BCR-ABL protein. After a chronic phase of production of too many white blood cells, CML typically evolves to the more aggressive phases referred to as accelerated phase and blast crisis. Ph+ ALL is a subtype of acute lymphoblastic leukemia that carries the Ph+ chromosome that produces BCR-ABL. It has a more aggressive course than CML and is often treated with a combination of chemotherapy and TKIs. The BCR-ABL protein is expressed in both of these diseases.

About Iclusig (as ponatinib hydrochloride)

Iclusig is a kinase inhibitor. The primary target for Iclusig is BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Iclusig was designed using ARIAD’s computational and structure-based drug design platform specifically to inhibit the activity of BCR-ABL. Iclusig targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved TKIs.

Indications

ICLUSIG is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) for whom other tyrosine kinase inhibitor (TKI) therapy is not appropriate, including CML or Ph+ ALL that is T315I mutation positive or where there is prior TKI resistance or intolerance.

Marketing authorization with conditions is based on response rate. There are no trials demonstrating increased survival or improvement in symptoms with ICLUSIG. In the pivotal trial, the majority of the hematological responses occurred within 1 month. Consider discontinuing ICLUSIG if a hematological response has not been achieved by 3 months (90 days).

ICLUSIG for this indication has been issued marketing authorization with conditions, pending the results of studies to verify its clinical benefit. Patients should be advised of the conditional nature of the authorization.

Contraindications

Do not use in patients who are hypersensitive to ponatinib or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.
Do not use in patients who have unmanaged cardiovascular risk factors, including uncontrolled hypertension. Hypertension may contribute to the risk of arterial thrombotic events. Blood pressure should be monitored and managed to avoid hypertension.
Do not use in patients who are not adequately hydrated and with uncorrected high uric acid levels.

Serious Warnings and Precautions

Iclusig has serious warnings and precautions for: vascular occlusion, heart failure, hemorrhage, hepatotoxicity, myelosuppression, and pancreatitis.

ICLUSIG should only be prescribed and monitored by a physician who has completed the certification with the ICLUSIG Controlled Distribution Program and who is experienced in the use of antineoplastic therapy and in the treatment of CML or Ph+ ALL.

Vascular Occlusion (arterial and venous thrombosis and occlusions), occurred in 24% (129/530) of ICLUSIG-treated patients with and without cardiovascular risk factors (including patients less than 50 years old). In clinical trials, serious treatment-emergent arterial thrombosis (cardiovascular, cerebrovascular, and peripheral vascular) and occlusions were seen in 14% of the ICLUSIG-treated patients including fatal myocardial infarction, fatal cerebral infarction, stroke, disseminated intravascular coagulation, and arterial stenosis sometimes requiring urgent revascularization procedures. Some of these events occurred within 2 weeks of starting treatment with ICLUSIG. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or consider discontinuation in patients who develop arterial thrombotic events.
Heart Failure (in some cases, fatal), including left ventricular dysfunction and ejection fraction decreases, occurred in 8% of ICLUSIG-treated patients, 5% of which were serious.
Hemorrhage events (some fatal) including intracranial hemorrhage, hemorrhagic gastritis, (fatal), hemorrhagic cerebral infarction (fatal). Most hemorrhagic events, but not all, occurred in patients with grade 4 thrombocytopenia.
Hepatotoxicity (including fatal acute hepatic failure) has been reported. Monitor hepatic function prior to and during treatment. Consider ICLUSIG dose interruption followed by dose reduction or discontinuation in patients with hepatotoxicity.
Myelosuppression (thrombocytopenia, neutropenia, and anemia).
Pancreatitis (7%) and elevations in amylase (2% grade 3 or greater) or lipase (12% grade 3 or greater) have been reported.

ICLUSIG has not been studied in patients with renal impairment.

Most Common Adverse Reactions

Overall, the very common adverse reactions (≥ 10%) were platelet count decreased, rash, dry skin, abdominal pain, neutrophil count decreased, headache, lipase increased, fatigue, constipation, myalgia, arthralgia, nausea, anemia, ALT increased, hypertension, and AST increased.

On April 6, 2015 Advaxis reported that it is entering into a clinical trial collaboration agreement with the Radiation Therapy Oncology Group (RTOG) Foundation to evaluate the safety and efficacy of Advaxis’s lead cancer immunotherapy, ADXS-HPV (ADXS11-001), in a pivotal Phase 2/3 anal cancer trial, which will be run by NRG Oncology (Press release, Advaxis, APR 6, 2015, View Source [SID:1234502925]). ADXS-HPV is an investigational Lm-LLO immunotherapy bioengineered to generate an immune response to the HPV-associated tumor specific oncogene.

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Under the proposed collaboration, RTOG Foundation, through its partnership with NRG Oncology, will conduct an adequate and well-controlled Phase 2/3 clinical trial of concurrent chemotherapy of mitomycin C/5FU and radiation therapy (CCRT) compared to CCRT combined with ADXS-HPV in the adjuvant treatment of high-risk locally advanced anal cancer.

Walter J. Curran, Jr., MD, RTOG Foundation Chairman of the Board and NRG Oncology Group Chair, commented, "The ability of ADXS-HPV to generate an immune response to the HPV-associated tumor specific oncogene offers the potential to benefit multiple cancers that are known to be caused by the HPV infection, including cervical cancer and anal cancer. We look forward to initiating this Phase 2/3 study in anal cancer and mirroring the encouraging results that the Gynecologic Oncology Group, now a part of NRG Oncology, has had in its clinical study of ADXS-HPV in cervical cancer."

David J. Mauro, MD, PhD, Executive Vice President and Chief Medical Officer of Advaxis, stated, "We are excited to enter this collaboration agreement with NRG Oncology and look forward to building on the initial results observed in the ongoing Phase 1/2 study of ADXS-HPV in anal cancer being conducted by Professor Howard Safran MD of Brown University Oncology Group. Although a relatively rare tumor, virtually all cases of squamous cell cancer of the anus are caused by HPV infection, and ADXS-HPV offers the potential to treat this often fatal malignancy."

About RTOG Foundation, Inc.

The Radiation Therapy Oncology Group (RTOG) has been an international leader in conducting Phase 2 and 3 multi-institutional clinical trials with a focus on radiation oncology issues. During its forty-plus year history, the group has repeatedly defined new standards of cancer care to improve the survival and quality of life of cancer patients and developed new processes for the study and application of innovative radiotherapy technologies. RTOG Foundation, Inc. is a Philadelphia based 501(c)(3) organization that continues its National Cancer Institute (NCI) funded research activities through NRG Oncology as one of its three founding members. RTOG also joins with corporate partners to conduct multicenter clinical trials systematically testing novel radiotherapy approaches combined with new classes of anti-cancer therapies and targeted agents. The group has completed a number of practice- and paradigm-changing trials in its primary disease sites: central nervous system, head & neck, lung, gastrointestinal (esophagus, stomach, pancreas, anal canal, and rectum), genitourinary (bladder and prostate), breast, and cervix.

About NRG Oncology

NRG Oncology conducts practice-changing, multi-institutional clinical and translational research to improve the lives of patients with cancer. Founded in 2012, NRG Oncology is a Pennsylvania-based nonprofit corporation that integrates the research strengths of the National Adjuvant Breast and Bowel Project (NSABP), the Radiation Therapy Oncology Group (RTOG) and the Gynecologic Oncology Group (GOG). The research organization seeks to carry out clinical trials with emphases on gender-specific malignancies including gynecologic, breast, and prostate cancers and on localized or locally advanced cancers of all types. NRG Oncology’s extensive research organization is comprised of multidisciplinary investigators including medical oncologists, radiation oncologists, surgeons, physicists, pathologists, and statisticians and encompasses more than 1300 research sites located world-wide with predominance in the United States and Canada. NRG Oncology is supported primarily through grants from the National Cancer Institute (NCI) and is one of five research groups in the NCI’s National Clinical Trials Network.

About ADXS-HPV

ADXS-HPV is Advaxis’s lead Lm-LLO immunotherapy product candidate for the treatment of HPV-associated cancers. It is currently under investigation in three HPV-associated cancers: invasive cervical cancer, head and neck cancer, and anal cancer. In cervical cancer, a completed Phase 2 study, ADXS-HPV demonstrated prolonged survival, objective tumor responses, and a manageable safety profile alone or in combination with chemotherapy, supporting further development of this Lm-LLO immunotherapy. The U.S. Food and Drug Administration granted an orphan drug designation for ADXS-HPV for HPV-associated Stage II-IV cervical cancer, head and neck cancer, and for anal cancer.