On August 18, 2015 Deciphera Pharmaceuticals, a clinical-stage biotechnology company focused on developing advanced kinase inhibitor treatments targeting the tumor cell and the tumor microenvironment, reported the publication of study results describing the preclinical profile of its Phase 1 anti-cancer product candidate, altiratinib, a balanced, spectrum-selective inhibitor of MET, TIE2, and VEGFR2 kinases (Press release, Deciphera Pharmaceuticals, AUG 18, 2015, View Source [SID:1234507291]).

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The article, which will appear in the September 2015 issue of Molecular Cancer Therapeutics, was pre-published on-line on August 18, 2015. Altiratinib is currently in Phase 1 clinical evaluation in cancer patients (NCT02228811).

In the article the authors describe how altiratinib’s balanced inhibition of the three key kinases, MET, TIE2, and VEGFR2 was achieved using Deciphera’s proprietary switch control kinase inhibitor platform. Moreover, altiratinib was shown to inhibit not only wild type MET, but also oncogenic mutant forms of MET not readily inhibited by other MET inhibitors in development. The ability to inhibit MET mutants during the course of treatment is a key component to altiratinib’s product profile, which Deciphera believes will provide more durable therapy for cancer patients compared to existing agents. MET mutations are driver mutations in certain cancers and can also arise as a resistance mechanism in patients with pre-existing MET amplifications, highlighting the need for durable inhibition of various forms of genomically altered MET.

The report further discloses altiratinib’s ability to block drug resistance mechanisms mediated by the tumor microenvironment. Through its balanced inhibitory potency, altiratinib was shown to inhibit three major evasive cancer (re)vascularization and resistance pathways with comparable single-digit nanomolar inhibitory potency, including HGF, ANG, and VEGF and to block tumor invasion and metastasis. Notably, in a glioblastoma tumor model known to exhibit these tumor microenvironment disease progression mechanisms, altiratinib was shown to double the overall survival of mice compared to vehicle control treated mice and, in combination with bevacizumab, to double survival compared to single-agent bevacizumab-treated mice.

"Altiratinib has a unique profile with the potential to provide cancer patients with a more durable therapy than currently approved and investigational kinase inhibitors in this space," said Daniel L. Flynn, Ph.D., Chief Scientific Officer and Founder of Deciphera Pharmaceuticals. "Already clinical oncologists are seeing the rise in secondary MET mutations, which confer resistance to current MET inhibitors. Altiratinib’s mechanism of action targets not only the wild type form of MET kinase, but also these various secondary mutations."

On August 18, 2015 OncoSec Medical Incorporated ("OncoSec") (NASDAQ: ONCS), a company developing DNA-based intratumoral cancer immunotherapies, reported enrollment of the first patient into the Phase II Investigator Sponsored Trial led by the University of California, San Francisco (UCSF) to assess the anti-tumor activity, safety, and tolerability of the combination of OncoSec’s investigational therapy, ImmunoPulse IL-12, and Merck’s approved anti-PD-1 agent, KEYTRUDA (pembrolizumab), in patients with unresectable metastatic melanoma (Press release, OncoSec Medical, AUG 18, 2015, View Source [SID:1234507287]).

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The primary endpoint is the best Overall Response Rate (bORR) of the combination regimen in patients whose tumors are characterized by low numbers of tumor-infiltrating lymphocytes (TILs).

"There is increasing evidence that tumors need to be inflamed and have TILs in order for anti-PD-1 therapies to be most effective," said Mai H. Le, MD, Chief Medical Officer of OncoSec. "Both preclinical and clinical evidence suggest that ImmunoPulse IL-12 can promote tumor immunogenicity. We anticipate that ImmunoPulse IL-12 will increase the proportion of patients who will respond to immune checkpoint inhibitors like KEYTRUDA and that the combination will have synergistic anti-tumor activity."

"This is the first study in the field of immuno-oncology to evaluate the combination of DNA-based interleukin-12 with electroporation and an anti-PD-1/PD-L1 inhibitor," said Punit Dhillon, CEO and President of OncoSec. "We believe the combination of OncoSec’s intratumoral cancer immunotherapy and checkpoint inhibitors has the potential to be a powerful approach in the fight against cancer."

This multi-center, open label, single-arm trial will enroll approximately 42 patients with unresectable, "low-TIL" metastatic melanoma. Alain Algazi, MD, a skin cancer specialist in the Melanoma Center at the UCSF Helen Diller Family Comprehensive Cancer Center, is the study’s sponsor and principal investigator. The key endpoints of the study include: best Overall Response Rate by RECIST v1.1 and immune related-Response Criteria (irRC); safety and tolerability; duration of response; 24-week landmark progression-free survival; median progression-free survival; and overall survival.

The treatment schedule for the trial follows the standard schedule for pembrolizumab. Pembrolizumab will be administered systematically once every three weeks and ImmunoPulse IL-12 will be administered on three separate days every six weeks. ImmunoPulse IL-12 employs intratumoral delivery of DNA-based IL-12 followed by electroporation. Merck will supply pembrolizumab, and OncoSec will provide ImmunoPulse IL-12.

To learn more about the trial, visit www.oncosec.com. Additional details can also be found at www.clinicaltrials.gov.

About Melanoma
Melanoma is one of the most dangerous forms of skin cancer and accounts for the vast majority of skin cancer deaths.1 When melanoma is caught early enough, surgical excision can be curative in the majority of Stage I and II melanomas. The overall 5-year survival rate for patients with localized melanoma is 98 percent in the United States.1 At later stages, malignant melanoma remains a deadly and frequently difficult to treat cancer. The overall 5-year survival rate for patients falls to 63 percent when the disease reaches the lymph nodes and 16 percent when the disease metastasizes to distant organs.1

Melanoma that has spread to distant sites may be treated with surgery, immunotherapy, chemotherapy and/or radiation therapy.1 Numerous chemotherapy regimens have been tested in melanoma with only modest success and limited overall survival benefit.2 Two approaches – checkpoint inhibitors and targeted kinase inhibitors – have demonstrated improvement in overall survival of patients compared to chemotherapy. 2

While immunotherapy can be extremely effective, the currently approved regimens do not benefit the majority of patients. However, early data of combination approaches with immunotherapies are promising.2 Researchers also continue to focus efforts on targeting pathways of T cell activation.3 The presence of CD8+ T cells seems to correlate with improved prognosis and long-term survival in solid malignancies, such as melanoma,4,5 thus many emerging experimental immunotherapies seek to enhance the tumor’s immunogenicity and increase the anti-tumor CD8+ T cell response.

On August 17, 2015 Seattle Genetics, Inc. (Nasdaq: SGEN) reported that the U.S. Food and Drug Administration (FDA) has approved ADCETRIS (brentuximab vedotin) for the treatment of patients with classical Hodgkin lymphoma (HL) at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation (Press release, Seattle Genetics, AUG 17, 2015, View Source [SID:1234507285]).

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The approval is based on a phase 3 clinical trial called AETHERA that was designed to compare up to 16 cycles (approximately one year) of ADCETRIS therapy administered every three weeks following auto-HSCT to placebo. The primary endpoint was met with a significant improvement in median progression-free survival (PFS) of 42.9 months (95% CI: 30.4, 42.9) for patients who received ADCETRIS versus 24.1 months (95% CI: 11.5, not estimable) for patients who received placebo, an improvement of 18.8 months (hazard ratio=0.57 [95% CI: 0.40, 0.81]; p-value=0.001). In addition, data from the AETHERA trial converted the U.S. accelerated approval of the relapsed classical HL indication to regular approval. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, which is expressed in classical HL and systemic anaplastic large cell lymphoma (sALCL), as well as other lymphoma subtypes. This is the third indication for ADCETRIS, which was granted accelerated FDA approval in August 2011 for two other indications: (1) treatment of Hodgkin lymphoma patients who fail autologous transplant or who fail at least two prior multi-agent chemotherapy regimens and are not autologous transplant candidates, and (2) treatment of systemic ALCL patients who fail at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

This Smart News Release features multimedia. View the full release here: View Source

ADCETRIS Product Photo (Photo: Business Wire)
ADCETRIS Product Photo (Photo: Business Wire)

Globally, there are more than 65,000 cases of HL diagnosed each year. Although frontline combination chemotherapy can result in durable responses, up to 30 percent of these patients fail frontline treatment. The standard for these patients is salvage therapy, followed by auto-HSCT; approximately half of all HL patients who undergo an auto-HSCT experience subsequent disease relapse.

"With this FDA approval, ADCETRIS is the first and only consolidation treatment option available to high risk classical Hodgkin lymphoma patients who undergo a transplant to preserve their post-auto-HSCT remissions," said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "This represents a meaningful advance for cancer patients and an important milestone for the ADCETRIS development program. Together with our three ongoing phase 3 trials and more than 30 additional clinical trials, this approval supports our goal to broadly establish ADCETRIS as the foundation of therapy for classical Hodgkin lymphoma and CD30-expressing malignancies."

"The FDA approval of brentuximab vedotin for post-autologous hematopoietic transplantation consolidation treatment in classical Hodgkin lymphoma patients with high risk of relapse or progression is a significant milestone for patients and physicians," said Craig Moskowitz, M.D., lead investigator on the trial and Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center. "Approximately half of all Hodgkin lymphoma patients who undergo an autologous hematopoietic stem cell transplant will relapse, representing a significant need for additional treatment options to improve progression free survival."

AETHERA Phase 3 Trial Demonstrates Significant Progression-Free Survival Benefit with ADCETRIS as Post-Transplant Consolidation in Hodgkin Lymphoma

The positive results from the phase 3 AETHERA trial were published in The Lancet in March 2015 and presented at the 56th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2014. A total of 329 HL patients at risk of relapse or progression were enrolled, including 165 on the ADCETRIS arm and 164 on the placebo arm. Patients eligible for enrollment in the AETHERA trial must have had a history of primary refractory HL, have relapsed within one year from receiving frontline chemotherapy and/or have had disease outside of the lymph nodes at the time of pre-auto-HSCT relapse. Results included:

The trial achieved its primary endpoint and demonstrated a significant increase in PFS per independent review facility, with a hazard ratio of 0.57 (95% CI: 0.40, 0.81) and a p-value of 0.001. Median PFS was 43 months (95% CI: 30.4, 42.9) for patients who received ADCETRIS versus 24 months (95% CI: 11.5, not estimable) for patients who received placebo.

The most common adverse events (≥20 percent), of any grade and regardless of causality, in the ADCETRIS arm were neutropenia (78 percent), peripheral sensory neuropathy (56 percent), thrombocytopenia (41 percent), anemia (27 percent), upper respiratory tract infection (26 percent), fatigue (24 percent), peripheral motor neuropathy (23 percent), nausea (22 percent), cough (21 percent) and diarrhea (20 percent). The most common adverse events (≥20 percent), of any grade and regardless of causality, in the placebo arm were neutropenia (34 percent), upper respiratory tract infection (23 percent) and thrombocytopenia (20 percent). Sixty-seven percent of patients on the ADCETRIS arm experienced peripheral neuropathy. Of those patients, 85 percent had resolution (59 percent) or partial improvement (26 percent) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range 0.1-138).

There are no post-marketing requirements as part of the U.S. approval. The AETHERA data have also been submitted to both the European Medicines Agency (EMA) and Health Canada requesting marketing authorization.

As part of a broad clinical development program, ADCETRIS is also being evaluated in three additional phase 3 clinical trials, referred to as ECHELON-1, ECHELON-2 and ALCANZA. Enrollment is expected to be completed in ECHELON-1 and ALCANZA during 2015 and in ECHELON-2 during 2016.

About ADCETRIS

ADCETRIS is being evaluated broadly in more than 30 ongoing clinical trials, including three additional phase 3 studies, in earlier lines of its approved classical HL and sALCL indications as well as in many additional types of CD30-positive malignancies, including cutaneous T-cell lymphoma, B-cell lymphomas and mature T-cell lymphomas.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS for intravenous injection has received approval from the FDA for three indications: (1) regular approval for the treatment of patients with classical HL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (2) regular approval for the treatment of classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (3) accelerated approval for the treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Health Canada granted ADCETRIS approval with conditions for relapsed or refractory HL and sALCL.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive HL following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. ADCETRIS has received marketing authorization by regulatory authorities in more than 55 countries. See important safety information below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

ADCETRIS (brentuximab vedotin) U.S. Important Safety Information

BOXED WARNING

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS (brentuximab vedotin).

Contraindication

ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.

Anaphylaxis and infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy.

Hematologic toxicities: Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with ADCETRIS. Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.

Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Closely monitor patients during treatment for the emergence of possible bacterial, fungal or viral infections.

Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment.

Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment.

Hepatotoxicity: Serious cases of hepatotoxicity, including fatal outcomes, have occurred with ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first dose of ADCETRIS or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.

Pulmonary Toxicity: Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, some with fatal outcomes, have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.

Serious dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Embryo-fetal toxicity: Fetal harm can occur. Advise pregnant women of the potential hazard to the fetus.

Most Common Adverse Reactions:

ADCETRIS was studied as monotherapy in 160 patients with relapsed classical HL and sALCL in two uncontrolled single-arm trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

ADCETRIS was studied in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT in a placebo-controlled randomized trial. The most common adverse reactions (≥20%) in the ADCETRIS-treatment arm (167 patients), regardless of causality, were neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea.

Drug Interactions:

Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations:

MMAE exposure and adverse reactions are increased in patients with moderate or severe hepatic impairment or severe renal impairment. Avoid use.

For additional Important Safety Information, including Boxed WARNING, please see the full Prescribing Information for ADCETRIS at View Source

About Classical Hodgkin Lymphoma

Lymphoma is a general term for a group of cancers that originate in the lymphatic system and is the most common type of blood cancer. There are two major categories of lymphoma: HL and non-Hodgkin lymphoma. Classical HL is distinguished from other lymphomas by the characteristic presence of CD30-positive Reed-Sternberg cells. The Reed-Sternberg cell generally expresses CD30.

According to the American Cancer Society, approximately 9,050 cases of HL will be diagnosed in the United States during 2015 and more than 1,150 will die from the disease.