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Juno Announces FDA Acceptance of Investigational New Drug Application for JCAR017 in Relapsed/Refractory B Cell Non-Hodgkin Lymphoma

On June 29, 2015 Juno reported the U.S. Food and Drug Administration (FDA) accepted the Company’s investigational new drug (IND) application for JCAR017 for patients with relapsed/refractory (r/r) B cell non-Hodgkin lymphoma, or NHL (Press release, Juno, JUN 29, 2015, View Source [SID:1234506005]). JCAR017 is a chimeric antigen receptor (CAR) T cell product candidate targeting CD19, a protein expressed on the surface of most B cell leukemias and lymphomas.

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The IND enables Juno to initiate a multi-center Phase I trial exploring JCAR017 for r/r NHL, scheduled to begin in 2015, with the potential to advance to a registration trial in 2016.

"Based on the encouraging results of JCAR017 in pediatric acute lymphoblastic leukemia, we are excited to begin investigating this product candidate in non-Hodgkin lymphoma," said Mark Frohlich, M.D., Juno EVP of development and portfolio strategy. "FDA acceptance of the JCAR017 IND for this multi-institutional study is an important milestone for Juno. Together with our planned fully-human CD19 CAR-T cell trial, combination study with AstraZeneca’s anti-PDL-1 antibody, and ongoing translational clinical trial with JCAR014, it will provide important biologic insights that will inform our future strategies."

In collaboration with Seattle Children’s Research Institute, Juno continues to investigate JCAR017 in pediatric patients with r/r acute lymphoblastic leukemia (ALL). Results of a Phase I study to date demonstrated 91 percent of patients achieved a complete remission, all of which were documented by flow cytometry. Adverse events were consistent with what has been previously reported. The results were presented in an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2015 in Philadelphia.

About Juno’s Chimeric Antigen Receptor (CAR) and T Cell Receptor (TCR) Technologies
Juno’s chimeric antigen receptor (CAR) and T cell receptor technologies (TCR) genetically engineer T cells to recognize and kill cancer cells. Juno’s CAR T cell technology inserts a gene for a particular CAR into the T cell, enabling it to recognize cancer cells based on the expression of a specific protein located on the cell surface. Juno’s TCR technology provides the T cells with a specific T cell receptor to recognize protein fragments derived from either the surface or inside the cell. When either type of engineered T cell engages the target protein on the cancer cell, it initiates a cell-killing response against the cancer cell.

CytRx Announces Presentation of Interim Phase 2 Data for Aldoxorubicin for HIV-Related Kaposi’s Sarcoma

On June 29, 2015 CytRx reported the presentation of interim results from its ongoing open-label Phase 2 pilot study evaluating the efficacy and safety of aldoxorubicin for the treatment of Kaposi’s Sarcoma (KS) in HIV-infected patients (Press release, CytRx, JUN 29, 2015, View Source [SID:1234506004]). The data will be presented on Wednesday, July 1, 2015 during a poster session at the 18th International Workshop on Kaposi’s Sarcoma Herpesvirus (KSHV) and Related Agents in Hollywood, Florida.

For the study, patients with biopsy-confirmed KS were administered 100 or 150 mg/m2 aldoxorubicin (75 or 112 mg/m2 doxorubicin equivalents) IV every three weeks. At the time of presentation, preliminary analyses were available for nine patients who received at least six cycles of drug (mean = 6.3 cycles). Four patients had received prior Doxil chemotherapy. Of these 9 patients, 6 (67%) demonstrated a partial response (PR) to aldoxorubicin at the end of study visit (EOS), and 7 (78%) demonstrated PR within 4 months of EOS. Doxorubicin could be detected in all tumor biopsies and higher doxorubicin concentrations were demonstrated within KS lesions relative to skin next to the lesions for 3/4 (75%) patients for whom adequate tissue was available for analysis. Five of 6 (83%) patients receiving aldoxorubicin and for whom data are available exhibited reduced intratumoral viral loads during therapy. A subset of patients also exhibited improvements in quality of life during treatment, and all patients exhibited either improvement or stability in immunologic and virologic HIV treatment parameters. Aldoxorubicin was well-tolerated, with only 2 patients (22%) experiencing a grade 4 adverse event (transient neutropenia and anemia), and overall AEs (44%) were mild and compared favorably with AE rates from other trials enrolling KS patients representing urban, minority-predominant populations.

"KS remains an important cause of morbidity and mortality for HIV-infected patients worldwide, yet significant toxicities limit drug exposure and outcomes for many patients when antiretroviral therapy is combined with standard treatments like liposomal doxorubicin (Doxil)," said Chris Parsons, MD, Associate Professor in the Departments of Medicine and Microbiology, Immunology, & Parasitology at the Louisiana State University Health Sciences Center, and principal investigator of the study. "These data demonstrate aldoxorubicin’s ability to leverage cancer biology to preferentially release chemotherapeutic drugs in tumors, thereby limiting toxicity, increasing drug exposure and improving outcomes. We remain highly encouraged by the activity and tolerability of aldoxorubicin in this study, and look forward to its continued enrollment and final results."

This open-label Phase 2 clinical trial is expected to enroll up to 30 patients, randomly assigned to two equally sized treatment arms which will receive aldoxorubicin at 100 or 150 mg/m2 by 30-minute intravenous infusion. Because the KS patients in the study have compromised immune systems, the aldoxorubicin dosages administered in the trial are lower than those administered in the Company’s clinical testing of aldoxorubicin in patients with soft tissue sarcomas. Patients with advanced KS receive aldoxorubicin on day 1, then every 3 weeks until evidence of tumor progression, unacceptable toxicity or withdrawal of consent. The primary objectives of preliminary efficacy include evaluation of the size, number and nodularity of skin lesions, change in size and number of lung lesions and changes in the number of tumor cells that express viral DNA (Kaposi sarcoma-associated herpesvirus, the etiologic agent of KS). The Company is also evaluating the level of aldoxorubicin uptake into lesions. Safety is being assessed through monitoring of adverse events and the ability to remain on assigned treatment. The trial is being conducted at the Louisiana State University Health Sciences Center in New Orleans, LA.

KS is an orphan indication in the U.S.

About Kaposi’s Sarcoma

Kaposi sarcoma is a cancer that causes lesions (abnormal tissue) to grow in the skin; the mucous membranes lining the mouth, nose, and throat; lymph nodes; or other organs. The lesions are usually purple and are made of cancer cells, new blood vessels, red blood cells, and white blood cells. Kaposi sarcoma is different from other cancers in that lesions may begin in more than one place in the body at the same time. KS remains the most common HIV-associated tumor worldwide. The condition is also endemic in certain parts of Central Africa and Central and Eastern Europe.

About Aldoxorubicin

The widely used chemotherapeutic agent doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifically to circulating albumin, the most plentiful protein in the bloodstream. Protein-hungry tumors concentrate albumin, thus increasing the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. This allows for greater doses (3 ½ to 4 times) of doxorubicin to be administered while reducing its toxic side effects. In studies thus far there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of drug well in excess of 2,000 mg/m2.

Independent Data Safety and Monitoring Board Recommends Continuation of Celldex’s Phase 3 Study of RINTEGA(R) (rindopepimut) in Newly Diagnosed Glioblastoma

On June 29, 2015 Celldex Therapeutics that an independent Data Safety and Monitoring Board (DSMB) recommended continuation of the Phase 3 ACT IV study of RINTEGA (rindopepimut) in patients with newly diagnosed glioblastoma (Press release, Celldex Therapeutics, JUN 29, 2015, View Source [SID:1234506002]).

The ACT IV study is a randomized, double-blind, placebo controlled study of rindopepimut plus GM-CSF added to standard of care temozolomide in patients with newly diagnosed, surgically resected, EGFRvIII-positive glioblastoma. 745 patients were enrolled into ACT IV to reach the required 374 patients with minimal residual disease (assessed by central review) needed for analysis of the primary overall survival endpoint. All patients, including those with disease that exceed this threshold, will be included in a secondary analysis of overall survival as well as analyses of progression-free survival, safety and tolerability, and quality of life. The timing of the overall survival primary endpoint data is event-driven. Interim analyses assessing safety, futility and efficacy conducted by an independent DSMB were prespecified at 50 percent and 75 percent of events.

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As previously announced, the second interim analysis is expected to occur in late 2015/early 2016.

RINTEGA is a registered trademark of Celldex Therapeutics.

About RINTEGA

RINTEGA is an investigational therapeutic vaccine that targets the tumor specific oncogene EGFRvIII, a functional and permanently activated variant of the epidermal growth factor receptor (EGFR), a protein that has been well validated as a target for cancer therapy. Expression of EGFRvIII correlates with increased tumorigenicity in mouse models and poor long term survival in clinical studies of patients with glioblastoma (GBM). In addition, EGFRvIII-positive cells are believed to stimulate proliferation of non-EGFRvIII cells through IL-6 cell-to-cell signaling and to release microvesicles containing EGFRvIII, which can merge with neighboring cells, transferring tumor-promoting activity. EGFRvIII expression may also be associated with tumor stem cells that have been identified in GBM. These stem cells contribute to resistance to cytotoxic therapy and tumor recurrence. EGFRvIII is expressed in tumors in about 30% of patients with GBM. It has not been detected at a significant level in normal tissues; therefore, targeting of this tumor-specific molecule is not likely to impact healthy tissues.

Three Phase 2 trials of RINTEGA—ACTIVATE, ACT II, and ACT III—have been conducted in newly diagnosed EGFRvIII-positive GBM and have shown consistent improvements in both overall survival and progression-free survival compared to matched historical controls. The most common adverse events for RINTEGA include injection site reactions, fatigue, rash, nausea and pruritus. RINTEGA is currently being studied in two clinical trials in EGFRvIII-positive GBM—an international Phase 3 study called ACT IV in newly diagnosed GBM and a Phase 2 study called ReACT in recurrent GBM. In February 2015, the U.S. Food and Drug Administration (FDA) granted RINTEGA Breakthrough Therapy Designation for the treatment of adult patients with EGFRvIII-positive glioblastoma (GBM).

Lilly and Immunocore Announce Immunotherapy-based Clinical Trial Collaboration in Melanoma

On June 29, 2015 Eli Lilly and Immunocore reported that they have entered into an immunotherapy-based clinical trial collaboration to explore the utility of Immunocore’s lead T cell receptor-based investigational therapeutic, IMCgp100, in combination with Lilly’s galunisertib (LY2157299) and merestinib (LY2801653) for the treatment of melanoma (Press release, Eli Lilly, JUN 29, 2015, View Source [SID:1234506000]). The goal of the collaboration is to identify combination regimens that provide synergies in efficacy and durability in patients with metastatic cutaneous and uveal melanomas.

Under the terms of the agreement, Immunocore and Lilly will conduct a Phase Ib/II clinical study evaluating the safety and preliminary efficacy of IMCgp100 in combination with galunisertib in metastatic cutaneous melanoma. A second Phase Ib/II study will be conducted combining IMCgp100 with merestinib in metastatic uveal melanoma. Lilly will act as trial sponsor. These studies are anticipated to begin in 2016. No financial terms were disclosed.

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IMCgp100 and galunisertib are members of a new class of cancer treatments known as immunotherapies, which are designed to enhance the body’s own immune system in fighting cancer and whose mechanisms of action have the potential to be complementary. IMCgp100 is Immunocore’s most advanced Immune mobilizing mTCR Against Cancer molecules (ImmTAC), which are a novel class of bi-specific biologic drugs based on T cell receptors (TCRs) with ultra-high affinity for intracellular and extracellular cancer targets. Lilly’s galunisertib is a small molecule inhibitor of TGF beta R1 kinase that in vitro selectively blocks TGF beta signaling. TGF beta promotes tumor growth, suppresses the immune system and increases the ability of tumors to spread in the body. Merestinib is Lilly’s small molecule multi-kinase inhibitor that in vitro selectively blocks signaling of MET, MST1R (RON), AXL, and MKNK1/2, pathways that potentially play a role in metastatic uveal melanoma.

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"This collaboration with Immunocore underscores Lilly’s commitment to discovering the potential of combination therapies, which will be key to the future of cancer care for people fighting diseases such as melanoma," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "Lilly is building a robust portfolio of potential advances in immunotherapy through our own research as well as with strategic collaborations like Immunocore."

Immunocore and Lilly entered into a co-discovery and co-development collaboration, announced in July 2014, to research and potentially develop other novel T cell-based cancer therapies built on Immunocore’s ImmTAC platform.

"We are very pleased to be able to announce a second collaboration with Lilly after entering into a collaboration last year," said Eliot Forster, chief executive officer of Immunocore. "Combining our ImmTAC, IMCgp100 with Lilly’s galunisertib and merestinib has the potential to transform the treatment of metastatic cutaneous and uveal melanoma. Immunocore is committed to the development of IMCgp100 in metastatic uveal and cutaneous melanoma where there is such great unmet medical need."

Immunocore recently announced clinical efficacy data in a Phase I/IIa trial with IMCgp100 in patients with advanced melanoma, as well as in the expansion cohort with uveal melanoma.

About Melanoma

Melanoma is a cancer that begins in the melanocytes. Other names for this cancer include malignant melanoma and cutaneous melanoma. Most melanoma cells still make melanin, so melanoma tumors are usually brown or black. But some melanomas do not make melanin and can appear pink, tan, or even white.

Melanomas can develop anywhere on the skin, but they are more likely to start on the trunk (chest and back) in men and on the legs in women. The neck and face are other common sites.

Melanoma is much less common than basal cell and squamous cell skin cancers, but it is far more dangerous. Like basal cell and squamous cell cancers, melanoma is almost always curable in its early stages. But it is much more likely than basal or squamous cell cancer to spread to other parts of the body if not caught early.[i]

According to the American Cancer Society’s estimates for melanoma in the United States for 2015, about 73,870 new melanomas will be diagnosed (about 42,670 in men and 31,200 in women); and about 9,940 people are expected to die of melanoma (about 6,640 men and 3,300 women).[ii]

Uveal (or ocular) melanoma is a cancer of the eye diagnosed in approximately 2,000-2,500 adults annually in the United States. In both the U.S. and Europe, this equates to about 5-7.5 cases per million people per year and, for people over 50 years old, the incidence rate increases to around 21 per million per year.[iii]

About IMCgp100 and ImmTACs

Immunocore’s proprietary technology is focused on small protein molecules called ImmTACs (Immune mobilizing mTCR Against Cancer) that enable the immune system to recognize and kill cancerous cells.

Immunocore’s ImmTACs, a new class of drug with ultra-high affinity for intracellular cancer targets, are synthetic, soluble T cell receptors (TCRs) that recognize diseased cells containing disease specific targets. The ImmTACs enable circulating T cells to selectively identify and kill diseased cells. The ImmTAC platform is unique and has very high specificity and potency as well as broad applicability to a wide range of intracellular targets. ImmTACs can access up to nine-fold more targets than typical antibody-based therapies, including monoclonal antibodies.

TCRs naturally recognize diseased cells and Immunocore’s world-leading competitive advantage is its ability to engineer high affinity TCRs and link them to an antibody fragment that activates a highly potent and specific T cell response to recognize and destroy cancer cells.

The most advanced ImmTAC, IMCgp100, is currently in Phase IIa clinical trials for the treatment of late stage melanoma. Following completion of a Phase I study at the end of 2013, Immunocore initiated a Phase IIa study to optimize the dosing regimen of IMCgp100. Immunocore has a growing internal pipeline of ImmTACs addressing many different cancer types and has developed a broad database of intracellular cancer targets.

About Galunisertib (LY2157299)

Galunisertib is a TGF beta R1 kinase inhibitor that in vitro selectively blocks TGF beta signaling. TGF beta promotes tumor growth, suppresses the immune system and increases the ability of tumors to spread in the body.

About Merestinib (LY2801653)

Merestinib is Lilly’s multi-kinase inhibitor that in vitro selectively blocks signaling of MET, MST1R (RON), AXL, and MKNK1/2.

The Leukemia & Lymphoma Society Accelerates Milestone Payment Associated with the Phase 3 Study of CPX-351 in High Risk (Secondary) AML

On June 29, 2015 Celator Pharmaceuticals reported that The Leukemia & Lymphoma Society (LLS) is accelerating a portion of the final payment linked to the Phase 3 study of CPX-351 (cytarabine:daunorubicin) liposome injection, Celator’s lead product candidate, for the treatment of patients with high-risk (secondary) acute myeloid leukemia (AML) (Press release, Celator Pharmaceuticals, JUN 29, 2015, View Source [SID:1234505999]).

LLS has moved forward payment of $400,000 originally attached to the final overall survival analysis milestone and added it to the milestone payment for induction response rate analysis, thereby increasing the payment from the original amount of $500,000 to $900,000. This brings the total LLS funding paid to date associated with the Phase 3 study to $4.9 million.

The financial support provided by the LLS Therapy Acceleration Program (TAP) has been important in expediting the completion of the Phase 3, multicenter trial of CPX-351 versus conventional cytarabine plus daunorubicin in older patients with untreated high risk (secondary) AML. Enrollment in the study was completed ahead of schedule, and positive induction response results were announced earlier this month. The overall survival results, the primary endpoint of the study, are expected in the first quarter of 2016. This study is planned to support a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) expected in the second half of 2016.

"We continue to be very pleased with the progress and positive outcomes Celator has achieved with the development of CPX-351," said Louis DeGennaro, Ph.D., LLS’s chief executive officer. "We felt it appropriate to accelerate our payments to assist Celator in completing the activities necessary to file the NDA with the FDA as soon as possible once the overall survival data become available. We are optimistic for a successful outcome of the Phase 3 study and want to help accelerate the availability of promising therapies such as CPX-351 to these patients who are in dire need of improved outcomes."

As part of a 2009 partnership, LLS provided $4.1 million to help fund Celator’s Phase 2 clinical development program, which included two randomized, controlled studies. The positive results from those two studies were used to help design the current Phase 3 study. LLS’s TAP program supports private sector and academic-based projects with the goal of advancing investigational therapies with high prospects for providing near-term benefit to patients with blood cancers.

"This additional funding comes at an opportune time," said Scott Jackson, Celator’s chief executive officer. "With the recent announcement of positive induction response rate results for our Phase 3 study, we continue to move forward with our preparations for an NDA filing and ultimately commercialization of CPX-351 in the United States. These activities will benefit from the earlier availability of TAP funds and with positive overall survival results in our Phase 3 study, CPX-351 will be available to AML patients as soon as possible. Our partnership with LLS, which began back in 2008, has been extremely productive towards that end."

About CPX-351
CPX-351 (cytarabine:daunorubicin) Liposome for Injection represents an innovative approach to developing combinations of drugs, in which drug molar ratios with synergistic anti-tumor activity are co-encapsulated in a drug delivery vehicle in order to maintain the desired ratio following administration. CPX-351 has been granted orphan drug status by the U.S. Food and Drug Administration and the European Commission for the treatment of Acute Myeloid Leukemia (AML). Celator has conducted two randomized, controlled, Phase 2 studies with CPX-351. The first study was conducted in newly diagnosed elderly AML patients and the second study was conducted in patients with AML in first relapse. In both Phase 2 studies, treatment with CPX-351 resulted in significant improvements in response rates, 60-day mortality, and overall survival in the highest risk patients. The Leukemia & Lymphoma Society has partnered with Celator in the development of CPX-351 starting in Phase 2 and continuing in Phase 3.

About Acute Myeloid Leukemia (AML)
LLS defines AML as a quickly progressing disease in which too many immature white blood cells (not lymphocytes) are found in the blood and bone marrow. According to Cancer Facts and Figures, in 2015 approximately 20,830 new cases of AML will be diagnosed in the United States and 10,460 deaths will occur from the disease.

About The Leukemia & Lymphoma Society
The Leukemia & Lymphoma Society (LLS) is the world’s largest voluntary health agency dedicated to blood cancer. The LLS mission: Cure leukemia, lymphoma, multiple myeloma, and improve the quality of life of patients and their families. LLS funds lifesaving blood cancer research around the world, provides free information and support services, and is the voice for all blood cancer patients seeking access to quality, affordable, coordinated care.