On November 11, 2016 TRACON Pharmaceuticals (NASDAQ:TCON), a clinical stage biopharmaceutical company focused on the development and commercialization of novel targeted therapeutics for cancer, wet age-related macular degeneration and fibrotic diseases, reported updated data from the Company’s Phase 1b/2 study of TRC105 and Votrient (pazopanib) at the Connective Tissue Oncology Society (CTOS) annual meeting taking place in Lisbon, Portugal (Press release, Tracon Pharmaceuticals, NOV 11, 2016, View Source [SID1234516501]).

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In poster presentation 2569989 entitled, "TRC105 in Combination with Pazopanib in Patients with Advanced Angiosarcoma," data from 18 angiosarcoma patients treated with either the combination of TRC105 (carotuximab) and Votrient, or with single agent TRC105 followed by the combination of TRC105 and Votrient, were presented:

For the initial five angiosarcoma patients enrolled in the original Phase 1b/2 clinical trial, the median progression-free survival (mPFS) is greater than 16.6 months. For the nine chemotherapy-refractory angiosarcoma patients treated with the combination of TRC105 and Votrient, three of whom had also previously progressed on Votrient treatment (and includes the initial five patients), mPFS is 5.6 months. Three of the nine patients remain on treatment, including two patients with durable complete responses (CRs), now on treatment for 19 and 26 months, respectively. For comparison, mPFS with single agent Votrient was 3.0 months with no CRs in a previously completed retrospective analysis of 30 chemotherapy-refractory and Votrient-naive angiosarcoma patients.
An additional group of nine angiosarcoma patients was enrolled and treated initially with single agent TRC105 followed by the combination of TRC105 and Votrient at progression. The mPFS in these nine patients treated initially with single agent TRC105 was similar to the mPFS reported in late-stage trials of single agent VEGF inhibitors, including Votrient and Nexavar (sorafenib). Four of the nine patients remain on study with either single agent TRC105 or the combination of TRC105 and Votrient, including one patient with a partial response.
TRC105 administered at its recommended Phase 2 dose of 10 mg/kg weekly was well-tolerated in combination with Votrient at its approved dose, which allowed for prolonged dosing without an increase in the frequency or severity of adverse events typical of each individual drug.
"The combination of TRC105 and Votrient has now been used to treat a total of 18 angiosarcoma patients and we continue to see encouraging signs of activity in this group of patients with limited therapeutic options," said Charles Theuer, M.D., Ph.D., President and CEO of TRACON. "Looking forward, we remain on track to initiate a randomized Phase 3 study of TRC105 with Votrient in patients with angiosarcoma at sites in the U.S. and Europe later this year or early 2017. Using the valuable input previously received from both U.S. and EU regulators, the trial will utilize an adaptive design that allows sample size re-estimation and patient enrichment. Importantly, we have submitted the trial design to the FDA for a Special Protocol Assessment (SPA)."

The poster is available on TRACON’s website at www.traconpharma.com.

About TRC105 (carotuximab)

TRC105 (carotuximab) is a novel, clinical stage antibody to endoglin, a protein overexpressed on proliferating endothelial cells that is essential for angiogenesis, the process of new blood vessel formation. TRC105 is currently being studied in multiple Phase 2 clinical trials sponsored by TRACON or the National Cancer Institute for the treatment of solid tumor types in combination with VEGF inhibitors. The ophthalmic formulation of TRC105, DE-122, is currently in a Phase 1/2 trial for patients with wet AMD. TRC205, a second generation antibody to endoglin, is undergoing preclinical testing in models of fibrosis.

On November 11, 2016 ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported new preclinical data that demonstrate the potential for enhanced activity when combining mirvetuximab soravtansine with immune checkpoint inhibition (Press release, ImmunoGen, NOV 11, 2016, View Source [SID1234516496]). These data will be presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 31st Annual Meeting, which is being held November 9-13 in National Harbor, Maryland.

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Mirvetuximab soravtansine is a first-in-class folate receptor alpha (FRα)-targeting ADC and is entering a Phase 3 trial, FORWARD I, as a single agent treatment for platinum-resistant ovarian cancer. Mirvetuximab is also being assessed in combination regimens with Keytruda, an immune checkpoint inhibitor, as well as Doxil, carboplatin and Avastin for both platinum-resistant and platinum-sensitive ovarian cancer in the Phase 1b/2 FORWARD II trial. The Company expects initial data from FORWARD II in mid-2017.

"We are committed to continuing to drive innovation in the research and development of ADCs for the treatment of cancer. These preclinical data reinforce the potential of combining mirvetuximab soravtansine with an immune checkpoint inhibitor, which we are evaluating as part of our FORWARD II trial," said Richard Gregory, Ph.D., executive vice president and chief scientific officer of ImmunoGen. "More broadly, these data suggest that ADCs using ImmunoGen’s maytansinoid technology may have an important role in promoting anti-tumor immunity in conjunction with immuno-oncology drugs."

In a poster presentation, the Company will report in vitro data showing that treatment of FRα-expressing tumor cells with mirvetuximab soravtansine activates monocytes, a type of antigen presenting cell (APC). Monocyte activation required both the antibody component of mirvetuximab soravtansine, which interacts with Fcγ receptors on APCs and its cancer-killing agent DM4, which promotes immunogenic cell death of the tumor cells. Activation of APCs in the presence of tumor neo antigen would trigger an anti-tumor T cell response that could be enhanced by immune checkpoint inhibition.

Poster Presentation
Title: "Treatment of Tumor Cells with Mirvetuximab Soravtansine, a FRα-Targeting Antibody-Drug Conjugate (ADC), Activates Monocytes Through Fc-FcγR Interaction and Immunogenic Cell Death"

Poster session #316: Saturday, November 12 at 11:45pm ET.
For additional information, visit the SITC (Free SITC Whitepaper) Annual Meeting website.

About Mirvetuximab Soravtansine
Mirvetuximab soravtansine (IMGN853) is the first FRα-targeting ADC. It uses a FRα-binding antibody to target the ADC specifically to FRα-expressing cancer cells and a potent anti-tumor agent, DM4, to kill the targeted cancer cells.

Mirvetuximab soravtansine is ImmunoGen’s lead program and is entering Phase 3 testing in the FORWARD I trial as a single agent for the treatment of platinum-resistant ovarian cancer. The candidate is also being assessed in combination regimens for both platinum-resistant and platinum-sensitive disease in Phase 1b/2 FORWARD II trial.

On November 11, 2016 Corvus Pharmaceuticals, Inc. (NASDAQ:CRVS), a clinical-stage biopharmaceutical company focused on the development and commercialization of novel immuno-oncology therapies, reported preliminary clinical safety and efficacy data from the dose-selection phase of its ongoing Phase 1/1b study of CPI-444 as a single agent and in combination with Genentech’s Tecentriq (atezolizumab),‎ a fully humanized monoclonal antibody targeting protein programmed cell death ligand 1 (PD-L1) (Press release, Corvus Pharmaceuticals, NOV 11, 2016, View Source [SID1234516492]). CPI-444 is a selective and potent inhibitor of the adenosine A2A receptor. The data were presented today in a poster session by John Powderly II, M.D., founder and president of the Carolina BioOncology Institute, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 31ST Annual Meeting & Associated Programs in National Harbor, Maryland. The poster can be accessed online here.

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"Although the data is early, we are seeing encouraging evidence of clinical activity with CPI-444 as a monotherapy and in combination with Tecentriq in patients with advanced refractory cancers," said Richard A. Miller an oncologist and co-founder, president and chief executive officer of Corvus. "We are excited about these preliminary data which show that several patients have achieved stable disease, one of the trial’s primary endpoints, with ongoing responses in cohorts receiving single agent and combination therapy. Tumor regression has been seen in patients who were naïve and refractory to prior treatments with anti-PD-1 or PD-L1 antibodies."

Initial safety and efficacy data from the first 46 patients enrolled in the dose-selection phase of the Phase 1/1b trial with a median follow up of two months were presented at the conference. All patients had failed all approved therapies for their disease, with a median of four prior treatment regimens (range: 1-5). Fifty-two percent of patients were refractory to prior treatment with anti-PD-1/PD-L1 antibodies. Enrolled patients had the following cancers: non-small cell lung (NSCLC), N=10; triple negative breast (TNBC), N=10; bladder, N=6; renal, N=5; melanoma, N=7; colorectal, N=3; prostate, N=2; and head and neck, N=3. The primary endpoints of the study are response rate and duration of clinical benefit (defined as complete response, partial response or stable disease). Patients are treated until disease progression or evidence of grade 3 or 4 toxicity.

Results presented showed:

Of the 32 patients who reached the first efficacy assessment at two months, 12 have shown stable disease and 20 have shown disease progression. Fourteen patients have not yet reached the two-month assessment. Six of the patients with disease progression remain on treatment based on investigator judgement that there is clinical benefit. Overall, 32 patients continue to receive treatment in the study and 14 have discontinued therapy.
Of the 12 patients with stable disease, several have shown ongoing tumor regression (1-20 percent reduction of the volume of indicator tumor lesions) by CT scan but have not yet reached the criteria for partial response (>30 percent reduction in tumor size per RECIST criteria). Seven of the 12 patients with stable disease received CPI-444 as a single agent.
Of the 10 patients with NSCLC, seven received single agent CPI-444. Five of seven evaluable patients have stable disease at two or more months (three of whom received single agent therapy). Nine patients remain on treatment and one patient has discontinued.
Of the five patients with RENAL CANCER, four received single agent CPI-444. Four patients remain on treatment and three of four evaluable patients have stable disease.
Two of four evaluable patients with BLADDER CANCER showed stable disease at first assessment, both of whom received single agent CPI-444.
Of the ten patients with TNBC, one of seven evaluable patients showed stable disease. Eight patients remain on treatment.
One of four evaluable patients with MELANOMA has stable disease with regression of cutaneous tumor lesions; this patient received single agent CPI-444.
One of two evaluable patients with PROSTATE CANCER treated with combination therapy has stable disease and showed a decrease in prostate-specific antigen (PSA) at 29 weeks; this patient has gained weight and requires significantly less narcotics for pain management.
CPI-444 has been well tolerated to date, with one patient treated with combination therapy experiencing a possibly drug-related serious adverse event. This patient developed autoimmune hemolytic anemia that resolved upon discontinuation of therapy.
Patients receiving CPI-444 100 mg twice daily had sustained, complete blockade of A2A receptor activity in peripheral blood immune cells.
"The data generated in this trial confirms the value of the protocol design and could provide us with an efficient route to future registration trials of CPI-444, particularly as a monotherapy or in combination with anti-PD1/PD-L1 in patients who are refractory to previous treatment with PD1/PD-L1 antibodies," said Ginna G. Laport, M.D., vice president, Clinical Development, at Corvus. "This initial part of the trial identified the optimum dose of CPI-444 that is being used in the second part of the trial, which is currently enrolling patients."

In a separate poster presentation (available online here), Corvus reported on the effects of treatment with CPI-444 on circulating blood immune cells and T-cell clonality. These results indicate:

Single agent treatment with CPI-444 leads to activation of T-cells in peripheral blood as well as increases in memory T-cells, key mediators of T-cell mediated immune responses.
Consistent with this observation, single agent CPI-444 leads to changes in the repertoire of T-cell clones in peripheral blood, consistent with induction of T-cell mediated immune responses. Limited changes in T-cell repertoires were seen in patients who progressed on treatment with either CPI-444 alone or in combination with atezolizumab.
Changes in T-cell repertoires were observed in anti-PD-1/PD-L1 treatment-naïve patients and in patients that were refractory to prior treatment with anti-PD-1/PD-L1 antibodies.
"The biomarker program is generating a wealth of information and we are encouraged by early data that suggest that CPI-444 treatment results in induction of T-cell mediated immune response in patients," said Ian McCaffery Ph.D., vice president, Translational Sciences, at Corvus. "Our goal is to understand the mechanisms of action and changes in patient immune status and these data suggest that we may be able to identify biomarkers to help define and identify the patients most likely to respond to CPI-444."

ABOUT THE PHASE 1/1B TRIAL
The Phase 1/1b trial is designed to examine the activity of CPI-444 as a single agent and in combination with Genentech’s Tecentriq (atezolizumab), an anti-PD-L1 antibody. Patients with non-small cell lung cancer, melanoma, renal cell cancer, triple-negative breast cancer, colorectal cancer, head and neck cancer, bladder cancer and prostate cancer who have failed all standard therapies are eligible.

The first part of the study (dose-selection) 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 Tecentriq). 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. The second part of the study is currently evaluating CPI-444 as a single agent in five disease-specific cohorts, and CPI-444 in combination with Tecentriq in five additional matched disease-specific cohorts. Corvus expects that each of these 10 cohorts will initially enroll 14 patients, but each cohort may be expanded based on efficacy.