On June 5, 2017 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company developing innovative cellular immunotherapies for the treatment of cancer, reported updated data from the TRANSCEND trial of JCAR017 in relapsed and refractory (r/r) aggressive B cell non-Hodgkin lymphoma (NHL) in a presentation at the 2017 Annual Meeting of the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) (Press release, Juno, JUN 5, 2017, View Source [SID1234519400]).

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JCAR017 is Juno’s investigative chimeric antigen receptor (CAR) T cell product candidate that targets CD19, a protein expressed on the surface of almost all B cell malignancies, and uses a defined composition of CD4 to CD8 T cells and a 4-1BB costimulatory domain, which differentiates it from other current CD19-directed CAR T product candidates.
"Today’s update of data from the TRANSCEND trial shows continued compelling results in patients with a wide range of aggressive NHL," said Sunil Agarwal, M.D., Juno’s President of Research and Development. "We are encouraged by the high rates of durable responses and the early survival data in these patients. We are also encouraged by the early safety data—a majority of patients treated experienced no cytokine release syndrome or neurotoxicity of any grade, which suggests the potential for outpatient administration."

The data presented today by principal investigator Jeremy Abramson, M.D., of Massachusetts General Hospital Cancer Center, were from the multicenter TRANSCEND trial (ASCO Abstract #7513), a Phase 1 study that has treated 71 patients with r/r aggressive B cell NHL, including those with diffuse large B cell lymphoma (DLBCL), follicular lymphoma grade 3B, or mantle cell lymphoma (MCL). This was a dose-finding study of JCAR017, following fludarabine/cyclophosphamide lymphodepletion. Patients were evaluated for pharmacokinetics, disease response, and safety outcomes, including those commonly associated with CAR T cell therapy, such as cytokine release syndrome (CRS) and neurotoxicity (NT). Patients in this study included those excluded from other trials, including those with ECOG 2 performance status, central nervous system (CNS) involvement of their lymphoma, and those relapsed after allogeneic bone marrow transplant.

Two analysis groups were presented for the DLBCL cohort, core and full. The core analysis (N=44) includes patients that represent the population that will move forward into the upcoming pivotal trial, which will begin in the second half of 2017. This includes patients with DLBCL (de novo and transformed from follicular lymphoma) that are ECOG Performance Status 0-1. The full analysis represents all r/r patients in the DLBCL cohort (N=55), including the 11 patients with poor performance status or niche subtypes of aggressive NHL. Both analysis groups are with conforming product, with at least one month follow up, and with a data cutoff date of May 4, 2017, for this presentation.

Key data and findings:
Core Group
Combining data across dose levels:
Overall response rate (ORR) is 86% (38/44) and the complete response (CR) is 59% (26/44).
Three-month ORR is 66% (21/32) and CR is 50% (16/32). Of three-month responders followed up at least six months, 90% (9/10) remain in response.

Early data suggest a dose response relationship at three months:
Dose level 1 (50 million cells) ORR is 58% (11/19) and CR is 42% (8/19).
Dose level 2 (100 million cells) ORR is 78% (7/9) and CR is 56% (5/9).
97% (37/38) of responding patients are alive and in follow up as of May 4, 2017.
2% (1/44) experienced severe CRS and 18% (8/44) experienced severe NT.
66% (29/44) did not experience any CRS or NT. No deaths were reported from CRS or NT.
There was one Grade 5 adverse event of diffuse alveolar damage, which the investigator assessed as related to fludarabine, cyclophosphamide, and JCAR017 treatment, occurring on day 23 in an 82-year-old subject who refused mechanical ventilation for progressive respiratory failure while neutropenic on growth factors and broad spectrum antibiotics and antifungals.

Full Dataset
Combining data across dose levels:
Best ORR is 76% (41/54) and CR is 52% (28/54).
Three-month ORR is 51% (21/41) and CR is 39% (16/41).
2% (1/55) experienced severe CRS and 16% (9/55) experienced severe NT. 60% (33/55) did not experience any CRS or NT. No deaths reported from CRS or NT.
Early data do not suggest a dose toxicity relationship at the doses tested:
Severe CRS rate is 3% (1/30) at dose level 1 and 0% (0/19) at dose level 2.
Severe NT rate is 20% (6/30) at dose level 1 and 11% (2/19) at dose level 2.
11% (6/55) received tocilizumab and 24% (13/55) received dexamethasone.
The most frequently reported treatment-emergent adverse events were neutropenia (35%), CRS (35%), and fatigue (31%).

Manufacturing
Product was available for 98% (86/88) of patients apheresed, and product that met specification was available for 89% (78/88) of patients.
About Juno’s Chimeric Antigen Receptor (CAR) and T Cell Receptor (TCR) Technologies
Juno’s CAR and TCR technologies 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. JCAR014 and JCAR017 are investigational product candidates and their safety and efficacy have not been established.

On June 5, 2017 ImmunoCellular Therapeutics, Ltd. ("ImmunoCellular") (NYSE MKT: IMUC) reported the presentation of data from the phase 1 clinical trial of ICT-121 in patients with recurrent glioblastoma (Press release, ImmunoCellular Therapeutics, JUN 5, 2017, View Source [SID1234519399]). The data from the 20-patient, open-label, multi-center study show that 6 of 20 patients are alive (as of April 2017; survival ranging from 10 to 24 months), and these patients will continue to be followed. As noted in the data presentation, ICT-121 was generally safe and well tolerated. As also noted, although diversity in patient disease severity resulting from a protocol amendment to expand patient eligibility makes interpretation of survival data difficult, the results are encouraging and warrant further investigation. Pending immune response data will provide insight into the potential effectiveness of ICT-121 in inducing the formation of cytotoxic T cells targeting CD133, a cancer stem cell marker. ICT-121 is a dendritic cell-based immunotherapy that specifically targets CD133 which is overexpressed in a wide variety of solid tumors, including glioblastoma as well as non-small cell lung, colon, ovarian, pancreatic and breast cancers.

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The phase 1 data were presented by Jeremy D. Rudnick, MD, a neurologist in the Johnnie L. Cochran, Jr. Brain Tumor Center in the Department of Neurology at Cedars-Sinai, in a poster titled, "Immunological targeting of CD133 in recurrent glioblastoma: A multi-center Phase I translational and clinical study of autologous CD133 dendritic cell immunotherapy." The data were presented at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), taking place in Chicago.

"The preliminary findings from this phase 1 trial are encouraging, especially in light of the lethality of recurrent glioblastoma and lack of therapeutic options for patients with this disease," said Dr. Rudnick. "We look forward to continuing to follow the patients in this study, and believe that ICT-121 is a potentially promising cancer immunotherapeutic agent."

The phase 1 multi-center trial of ICT-121 targeting CD133 assesses safety and tolerability (primary endpoint) and monitors overall survival and progression-free survival (secondary endpoints). ICT-121 is comprised of autologous dendritic cells that are loaded with two HLA-A2 restricted epitopes of the CD133 antigen. After surgical resection, the HLA-A2-positive patients with recurrent glioblastoma were treated with ICT-121 once a week for 4 weeks during the induction phase and then once every 2 months during the maintenance phase until disease progression, death, ICT-121 depletion or discontinuation. In addition to safety and survival data, the phase 1 trial also assesses immune response by using an ELISpot assay and examining cytokine mRNA expression in response ICT-121 treatment.

"We are encouraged by the preliminary phase 1 results of ICT-121, which we believe underscore the potential of our DC-based approach to cancer immunotherapy," said Anthony J. Gringeri, PhD, ImmunoCellular President and Chief Executive Officer. "We are grateful for the time and effort of the patients, investigators, and staff who supported this clinical study."

About Recurrent Glioblastoma and CD-133

A defining characteristic of glioblastoma is the high incidence of tumor recurrence, which is thought to be triggered by cancer stem cells. These tumorigenic cells tend to be resistant to irradiation and chemotherapeutic agents. The target antigen, CD-133, is overexpressed in glioblastoma tumors and has been identified as a marker for cancer stem cells. Recent clinical trials suggest that the short survival time for these patients emphasizes the important unmet medical need in this disease requiring additional strategic approaches. Dendritic cell immunotherapies, such as ICT-121, could provide benefit to patients by educating their immune systems to induce the formation of cytotoxic T cells that attack tumor cells bearing the target antigen. In addition to immediate attack on tumor cells present at dosing, a long-term memory response effective against tumor recurrence might be induced. Immunotherapy, such as ICT-121, that targets cancer stem cells could be an important treatment for this disease.

On June 5, 2017 Corvus Pharmaceuticals, Inc. (NASDAQ:CRVS), a clinical-stage biopharmaceutical company focused on the development and commercialization of novel immuno-oncology therapies, reported interim safety and efficacy results from the renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC) expansion cohorts in its ongoing Phase 1/1b study (Press release, Corvus Pharmaceuticals, JUN 5, 2017, View Source [SID1234519398]). The data showed that treatment with CPI-444 as a single agent and in combination with atezolizumab (Tecentriq) resulted in anti-tumor activity in patients resistant or refractory to prior treatment with anti-PD-(L)1 antibodies and patients with PD-L1 negative tumors. CPI-444 is a selective and potent inhibitor of the adenosine A2A receptor. Atezolizumab, developed by Genentech, a member of the Roche Group, is a monoclonal antibody designed to target and bind to a protein called PD-L1 (programmed death ligand-1).

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The interim data were presented today in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2017 Annual Meeting in Chicago by Lawrence Fong, M.D., Professor in Cancer Biology and Leader of the Cancer Immunotherapy Program at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.

"These preliminary results from the CPI-444 clinical trial show that targeting this novel immunosuppressive pathway can lead to both anti-tumor immune responses and clinical responses in patients who have progressed on anti-PD-(L)1 therapies," said Dr. Fong. "Lung and renal cell cancer patients who do not respond to treatment with PD-(L)1 therapies typically continue to progress rapidly and have very few options to manage their disease, creating a significant unmet need in cancer therapy. These data suggest that CPI-444, both as a single agent and in combination with atezolizumab, may induce tumor regression or disease control in these difficult-to-treat populations."

"The anti-tumor activity and durability of responses and disease control seen to date are encouraging, especially in patients who are resistant/refractory to prior anti-PD-(L)1 therapy and have PD-L1 negative tumors. No therapies are currently approved that can overcome resistance to anti-PD-(L)1 therapies and few, if any, immunotherapies in development have reported benefit in the PD-1 resistant/refractory setting," said Richard A. Miller, an oncologist and co-founder, president and chief executive officer of Corvus. "In addition to our previously announced cohort expansions, based on data reported here, we have met the pre-defined criteria for the second expansion to the maximum number of 48 patients in the RCC cohort receiving combination therapy. We look forward to continuing to evaluate patients with lung and renal cell cancer enrolled in the multiple expansion cohorts, as we believe that targeting the adenosine pathway could lead to new treatment options for patients in this setting."

KEY PATIENT DEMOGRAPHIC DATA

Interim safety and efficacy data on 75 patients with RCC (n=30) or NSCLC (n=45) enrolled in the Phase 1/1b study to date were presented. Of these, 73 percent of RCC patients and 82 percent of NSCLC patients were resistant or refractory to prior therapy with anti-PD-(L)1 antibodies. Of the RCC (n=19) and NSCLC (n=28) patients with archived samples available, 95 percent and 54 percent of patients, respectively, had PD-L1 negative tumors.

KEY STUDY RESULTS IN RCC PATIENTS

An infographic accompanying this announcement is available at View Source

• Best tumor response data for RCC patients are shown in a "waterfall" plot (Figure 1). There were two confirmed partial responses (PR) out of 22 evaluable patients.

One PR was in a patient treated with single agent CPI-444 who was resistant/refractory to prior anti-PD-(L)1 therapy and was PD-L1 negative.
One PR was in an anti-PD-(L)1 treatment-naïve patient treated with combination therapy. The PD-L1 status of this patient treated in combination was not available at the time of the presentation.
The duration of PRs, which are ongoing in these two patients, exceeds eight months and three months.
• 16 patients achieved stable disease, with six of these patients experiencing minor regressions (MR). Four of the patients that achieved an MR were resistant/refractory to prior anti-PD-(L)1 therapy. The remaining patients had progressive disease or progressed before their first CT scan was obtained.

Six patients have had disease control for more than six months (range: 6-12 months), with five of these six patients continuing on therapy (three single agent, two combination).
• For RCC patients with stable disease, an analysis of tumor growth kinetics demonstrated that several patients with documented tumor growth prior to study enrollment, had stabilization or regression of their tumors while receiving treatment with CPI-444, suggesting that treatment altered the behavior of tumor growth.

KEY STUDY RESULTS IN NSCLC PATIENTS

An infographic accompanying this announcement is available at View Source

• Best tumor response data for NSCLC patients are shown in a "waterfall" plot (Figure 2). There were two partial responses (PR) out of 34 evaluable patients.

One confirmed PR was in a patient treated with combination therapy who was resistant/refractory to prior anti-PD-(L)1 therapy and is PD-L1 negative. The PR is ongoing at six months.
One unconfirmed PR is in a patient who received the combination, was resistant/refractory to prior anti-PD-(L)1 therapy, is PD-L1 positive, and is ongoing at two months.
• 22 patients achieved stable disease. Four of the stable disease patients, all of whom were were resistant/refractory to prior anti-PD-(L)1 therapy, had MRs. The remaining patients had progressive disease or progressed before their first CT scan was obtained.

• Four patients with NSCLC, three of whom were resistant/refractory to prior anti-PD-(L)1 therapy, experienced disease control exceeding six months (two single agent, two combination). All of the patients continue on therapy.

SAFETY DATA
CPI-444 continues to be well tolerated to date, with observed adverse events similar to previous reports. For single-agent CPI-444 cohorts, the following Grade 1 and 2 adverse events occurred in 5 percent or more of patients: fatigue, nausea, pruritis, constipation, dizziness, hypertension and fever. For combination therapy cohorts, the following Grade 1 and 2 adverse events occurred in 5 percent or more of patients: fatigue, nausea, pruritis, rash and increase in liver enzymes. In the combination cohort, one patient developed reversible Grade 3 immune-related toxicities.

PHASE 1/1B TRIAL DESIGN
The Phase 1/1b trial is designed to select the dose, assess the safety and examine the activity of CPI-444 as a single agent and in combination with Genentech’s atezolizumab, an anti-PD-L1 antibody, in multiple histologies known to be sensitive to immuno-oncology agents. Patients with non-small cell lung cancer, melanoma, renal cell cancer, triple-negative breast cancer (TNBC), MSI-H colorectal cancer, head and neck cancer, bladder cancer and prostate cancer who have failed standard therapies are eligible. The efficacy endpoints of the study are response rate and disease control rate, which is defined as complete response, partial response (reduction of >30 percent tumor volume) or stable disease (change in tumor volume of between 20 percent growth of tumor and 30 percent reduction of tumor volume). Patients with minor tumor regressions are those with changes in tumor volume of 0 to ≤30 percent reduction in tumor volume. Patients are treated until disease progression or evidence of Grade 3 or 4 toxicity.

The dose-selection part of the study included four cohorts of 12 patients each (N=48) – three cohorts treated with single agent CPI-444 (100 mg twice daily for 14 days; 100 mg twice daily for 28 days; 200 mg once daily for 14 days) and one cohort treated with the combination (CPI-444 50 mg or 100 mg twice daily for 14 days combined with atezolizumab). A treatment cycle is 28 days. Based on biomarker analyses showing sustained, complete blockade of the adenosine A2A receptor in peripheral blood lymphocytes, and evidence of immune activation in circulating lymphocytes, an optimum single agent and combination dose of 100 mg twice a day for 28 days was selected for the second part of the study. As defined in the protocol, patients in the dose-selection stage of the trial receiving the dose and schedule selected for evaluation in the second part of the study are included in the disease-specific cohort efficacy analysis.

The second part of the study is evaluating CPI-444 as a single agent in five disease-specific cohorts (NSCLC, melanoma, RCC, TNBC and a category of "other" that includes MSI-H colorectal cancer, bladder cancer and prostate cancer) and CPI-444 in combination with atezolizumab in five additional matched disease-specific cohorts. Each of the 10 cohorts is initially enrolling 14 patients, but may be expanded based on efficacy. To date, RCC and NSCLC, both single agent and combination cohorts, have met the initial criteria for expansion to 26 patients. Recently, the combination cohort of patients with renal cell cancer met the second criteria for expansion to 48 patients.

On June 5, 2017 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported positive, mature results from the Company’s Phase 2 study of glembatumumab vedotin in patients with stage III/IV checkpoint inhibitor-refractory, and, if applicable, BRAF/MEK inhibitor-refractory metastatic melanoma (n=62) (Press release, Celldex Therapeutics, JUN 5, 2017, View Source [SID1234519397]). Glembatumumab vedotin is a fully human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (gpNMB), a protein overexpressed by multiple tumor types, including metastatic melanoma, where more than 80% of patients overexpress the marker. High tumor expression of gpNMB is associated with shorter metastasis-free survival and reduced overall survival.1 Study results were presented today in an oral presentation by Patrick A. Ott, M.D., Ph.D., Clinical Director of Dana-Farber Cancer Institute’s Melanoma Center and its Center for Immuno-Oncology, Assistant Professor of Medicine at Harvard Medical School and an investigator in the study, at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago.

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Study Highlights

Median overall survival (OS) for all patients was 9.0 months (95% CI: 6.1, 13.0).
As previously reported in October 2016, 7 of 62 (11%) patients experienced a confirmed response, and an additional three patients also experienced single timepoint partial responses. Since data were reported in October, one patient converted from a confirmed partial response to a confirmed complete response.
Patients who experienced rash in Cycle 1 experienced a more prolonged OS with a median of 15.8 months (p=0.026, HR=0.44) as compared to those who did not experience rash.
"It’s exciting to see clinical activity in this study as very few treatment options exist for melanoma patients who progress after immune checkpoint inhibitors and BRAF targeted therapy," said Dr. Ott. "The single-agent response rate observed in this study, including a complete response, and the duration of the objective responses continue to suggest that glembatumumab vedotin is an active agent in this disease. I am hopeful that leveraging the immune system with checkpoint inhibition in combination with the cytotoxic and immunologic cell death induced by glembatumumab vedotin could bring benefit to an even larger number of patients with melanoma, and I look forward to the outcome of these additional cohorts."

Phase 2 Study Single-agent Cohort Overview and Previously Presented Results

Patients enrolled in this single-agent, open-label cohort of glembatumumab vedotin presented with unresectable stage IV (n=62) melanoma. The median number of prior therapies was three (range of 1 to 8). All patients had been heavily pre-treated and had progressed during or after checkpoint inhibitor therapy, and almost all patients had received both ipilimumab (n=58; 94%) and anti-PD-1/anti-PD-L1 (n=58; 94%) therapy. Twelve patients presented with BRAF mutation, and fifteen had prior treatment with BRAF or BRAF/MEK targeted agents. Patients received glembatumumab vedotin every three weeks until disease progression or intolerance. The safety profile was consistent with prior studies of glembatumumab vedotin with rash, neutropenia and neuropathy experienced as the most significant adverse events.

As previously reported, the primary endpoint of the cohort (6 or more objective responses in the first 52 patients enrolled) was exceeded. Seven of 62 (11%) patients experienced a confirmed response, and an additional three patients also experienced single timepoint responses. The median duration of response was 6.0 months. A 52% disease control rate (patients without progression for greater than three months) was demonstrated, and median PFS for all patients was 4.4 months. Consistent with previous studies in melanoma and breast cancer, rash was associated with greater clinical benefit. Patients who experienced rash in Cycle 1 experienced a 21% confirmed response rate, a more prolonged PFS with a median of 5.5 months (p=0.006; HR=0.39) and a more prolonged OS with a median of 15.8 months (p=0.026, HR=0.44).

Pre-treatment tumor tissue was available for 59 patients. All samples were gpNMB positive, and 78% of patients had tumors with 100% of their epithelial cells expressing gpNMB. Given both the high level of expression and the intensity of expression across this patient population, identifying a potential population for gpNMB enrichment is not feasible; therefore, all patients with metastatic melanoma could be evaluated as potential candidates for treatment with glembatumumab vedotin in future studies.

Ongoing Cohorts Combining Glembatumumab Vedotin with Varlilumab or Checkpoint Inhibitor

In August 2016, the Company announced that the study protocol was amended to add a second cohort of patients to a glembatumumab vedotin and varlilumab combination. Varlilumab is Celldex’s fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade. This additional cohort has completed enrollment with data presentation expected in the fall of 2017. Celldex is now enrolling patients to a third arm in the study to assess a glembatumumab vedotin and checkpoint combination in patients who have previously progressed on checkpoint inhibitor. This rationale is strongly supported by preclinical data that suggest that the anti-tumor activity may be enhanced with the combination. In addition, due to their direct cytotoxic properties, microtubule-depolymerizing agents like MMAE also appear to convert tumor-resident tolerogenic dendritic cells into active antigen-presenting cells.2

The Company also intends to conduct exploratory analyses of pre-entry skin biopsies in future patients to investigate potential predictors of response to glembatumumab vedotin, given the association of rash and outcome.

About Glembatumumab Vedotin

Glembatumumab vedotin is a fully human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (gpNMB). gpNMB is a protein overexpressed by multiple tumor types, including breast cancer, melanoma, lung cancer, uveal melanoma and osteosarcoma. gpNMB has been shown to be associated with the ability of the cancer cell to invade and metastasize and to correlate with reduced time to progression and survival in breast cancer. The gpNMB-targeting antibody, CR011, is linked to a potent cytotoxic, monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary technology. Glembatumumab vedotin is designed to be stable in the bloodstream but to release MMAE upon internalization into gpNMB-expressing tumor cells, resulting in a targeted cell-killing effect. Glembatumumab vedotin is in development for the treatment of locally advanced or metastatic breast cancer with an initial focus in triple negative disease, stage III and IV melanoma, squamous cell lung cancer and uveal melanoma.

On June 5, 2017 Celldex Therapeutics, Inc. (Nasdaq:CLDX) reported data from the Phase 1 portion of a Phase 1/2 dose escalation and cohort expansion study examining the combination of varlilumab, Celldex’s CD27 targeting investigational immune-activating antibody, and Bristol-Myers Squibb’s anti-PD-1 immunotherapy Opdivo (nivolumab) (Press release, Celldex Therapeutics, JUN 5, 2017, View Source [SID1234519395]). Rachel E. Sanborn, M.D., Co-director of the Providence Thoracic Oncology Program; and Phase I Clinical Trials Program, at the Earle A. Chiles Research Institute, Providence Cancer Center, in Portland, Ore. presented results from the study in an oral presentation entitled, "Clinical Results with Combination of Anti-CD27 Agonist Antibody, Varlilumab, with Anti-PD1 Antibody Nivolumab in Advanced Cancer Patients" at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago. The primary objective of the Phase 1 portion (n=36) of the study was to evaluate the safety and tolerability of the combination. The Phase 2 portion of the study is expected to complete enrollment in early 2018.

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"Combining PD-1 inhibition with a potent T cell activating agent provides the opportunity to broaden the number of patients that benefit from checkpoint blockade," said Dr. Sanborn. "While early, we have evidence that this combination does not add toxicity, can turn some ‘immune-cold’ tumors hot, and may have clinical benefit, including in some patients who are not likely to respond to monotherapy. Further elucidating the role of intermittent versus chronic T cell activation through the comparison of alternate varlilumab dosing regimens is an essential component of the ongoing Phase 2 study and could be important in optimizing the potential of this combination."

Key Highlights

• The majority of patients enrolled in the study had PD-L1 negative tumor at baseline and presented with Stage IV, heavily-pretreated disease. 80% of patients enrolled presented with refractory or recurrent colorectal (n=21) or ovarian cancer (n=8), a population expected to have minimal response to checkpoint blockade.

• Combining the potent immune activator, varlilumab, with the PD-1 inhibitor, Opdivo, was well tolerated at all varlilumab dose levels tested without any evidence of increased autoimmunity or inappropriate immune activation.

• Notable disease control observed (stable disease or better for at least 3 months), considering the Stage IV patient population, contained mostly colorectal and ovarian cases (80%).

0.1 mg/kg varlilumab + 240 mg Opdivo: 1/5 (20%)
1 mg/kg varlilumab + 240 mg Opdivo: 5/15 (33%)
10 mg/kg varlilumab + 240 mg Opdivo: 6/15 (40%)
• Three partial responses (PR) observed.

A patient with PD-L1 negative, MMR proficient colorectal cancer, typically unlikely to respond to checkpoint blockade monotherapy, achieved a confirmed PR (presented with metastatic disease to the liver, adrenal gland, abdomen and mesenteric nodule and on study experienced a 95% decrease in target lesions, including resolution of 4/5 target lesions, one 6 mm mesenteric nodule remains). Following completion of combination treatment, the patient continues to receive treatment with Opdivo monotherapy at 22 months. The patients previously received two prior chemotherapy-based regimens, one of which also included EGFR-targeted therapy.
A patient with low PD-L1 (5% expression) squamous cell head and neck cancer achieved a confirmed PR (59% shrinkage) and experienced progression free survival of 6.7 months.
A patient with PD-L1 negative ovarian cancer experienced a single timepoint PR (49% shrinkage) but discontinued treatment to a dose-limiting toxicity (immune hepatitis, an event known to be associated with checkpoint inhibition therapy).
• Migration of immune cells to tumor observed.

Peripheral blood analysis consistent with varlilumab monotherapy, transient increase in inflammatory chemokines (CXCL10, MCP-1, MIP-1β and MIG) and prominent decreases in CD4 and Treg cells without clear association with dose observed.
Tumor biopsy analysis revealed the majority of patients had "cold" tumors at baseline (negative or low PD-L1 and low T cell infiltrate).
A subgroup analysis was conducted in patients with ovarian cancer based on an observed increase of PD-L1 and tumor-infiltrating lymphocytes in this patient population.
• In patients with paired baseline and on-treatment biopsies (n=13), only 15% were PD-L1 positive (≥ 1% tumor cells) at baseline compared to 77% during treatment (p=0.015).
• Patients with increased tumor PD-L1 expression and tumor CD8 T cells correlated with better clinical outcome with treatment (stable disease or better).
• Continuous activation by immune agonists may not be optimal as it could lead to immune exhaustion and dampen the effect of combination therapy. The Phase 2 portion of this study includes alternate varlilumab dosing regimens to evaluate continuous versus intermittent immune activation at higher and lower dose levels and varied frequency.

In April 2016, the trial advanced to the Phase 2 portion of the study and includes cohorts in colorectal cancer, ovarian cancer, head and neck squamous cell carcinoma, renal cell carcinoma and glioblastoma. Varied dosing schedules are being explored in the ovarian and head and neck cohorts. Celldex plans to complete enrollment across all cohorts in the first quarter of 2018 and will work with Bristol-Myers Squibb to present data from the Phase 2 study at a future medical meeting. The primary objective of the Phase 2 study is overall response rate for all cohorts except glioblastoma, where the primary objective is the rate of 12-month overall survival. Secondary objectives include pharmacokinetics assessments, determining the immunogenicity of varlilumab when given in combination with Opdivo and further assessing the antitumor activity of combination treatment, including duration of response, time to response, progression-free survival and overall survival. The study is being conducted by Celldex under a clinical trial collaboration with Bristol-Myers Squibb Company. The companies are sharing development costs.

About Varlilumab

Varlilumab is a fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade. 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 single-agent Phase 1 dose-escalation study, demonstrating potent immunologic activity consistent with its mechanism of action and antitumor activity in patients with advanced, refractory disease. No maximum tolerated dose was reached, and minimal toxicities were observed.

Opdivo is a registered trademark of Bristol-Myers Squibb.