On November 11, 2017 Nektar Therapeutics (Nasdaq: NKTR) and Bristol-Myers Squibb (NYSE: BMY) reported the first presentation of data from the PIVOT-02 Phase 1/2 Study, which is designed to evaluate the combination of Bristol-Myers Squibb’s Opdivo (nivolumab) with Nektar’s investigational medicine, NKTR-214. The initial results presented at the 2017 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting reported both safety and efficacy data for patients enrolled in the dose-escalation phase of the trial (Press release, Nektar Therapeutics, NOV 11, 2017, View Source [SID1234521946]).

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"These initial findings underscore the potential benefit of the combination of Opdivo and NKTR-214 across several tumor types," said Fouad Namouni, M.D., Head of Oncology Development, Bristol-Myers Squibb. "We believe that a combination regimen which utilizes two different, complementary, and non-overlapping mechanisms designed to harness the body’s own immune system to fight cancer has the potential to benefit patients and should be the subject of additional research."

Opdivo is a PD-1 immune checkpoint inhibitor designed to overcome immune suppression. NKTR-214 is an investigational immuno-stimulatory therapy designed to expand and activate specific cancer-fighting T cells and natural killer (NK) cells directly in the tumor micro-environment and increase expression of cell-surface PD-1 on these immune cells.

"In the dose-escalation stage of the PIVOT trial, we’ve observed important response rates across all three tumor types – melanoma, renal cell carcinoma and non-small lung cancer – in both PD-L1 positive and PD-L1 negative patients," said Mary Tagliaferri, M.D., Senior Vice President of Clinical Development at Nektar Therapeutics. "All patients with responses in the trial continue on treatment. Of note, we observed responses in 3 of 4 Stage IV non-small cell lung cancer patients whose tumors did not express PD-L1 and who had progressed on prior chemotherapy, including one patient who experienced a complete response. In the combination treatment, there were no Grade 3 or higher immune-mediated adverse events at the recommended Phase 2 dose or below. Nektar and Bristol are now actively enrolling patients in the Phase 2 expansion part of the PIVOT study in 5 different tumor types."

A copy of the full data presentation from Dr. Diab’s oral session is available on Nektar’s corporate website at View Source

A total of 38 patients were enrolled in the dose-escalation phase of the ongoing PIVOT study in a number of dose cohorts. Responses were measured per RECIST 1.1 for efficacy-evaluable ( > 1 on treatment scan) patients as of November 2, 2017.

Highlights from the oral presentation include:

Advanced Treatment-Naïve 1L Melanoma Patients (Stage IV):
Responses were observed in 7/11 (63%) efficacy-evaluable patients (2 CR and 5 PR) ◊. Median time to response was 1.7 months. DCR, also known as disease control rate (CR + PR + 3 SD), was 91%. All 7 patients with responses continue on treatment in the trial.
Advanced Treatment-Naïve 1L Renal Cell Carcinoma Patients (Stage IV):
For patients with one or more baseline scans, responses were observed in 6/13 patients (46%) (1 CR+ and 5 PR). DCR (CR + PR + 5 SD) was 85%. Median time to response in these patients was 1.9 months. For patients with two or more scans available, responses were observed in 6/10 patients (60%) (1 CR, 5 PR, 2 SD). All 11 patients with disease control (CR, PR or SD) continue on treatment in the trial.
Advanced 2L Renal Cell Carcinoma Patients (Stage IV, I-O Naïve)
For patients with one or more baseline scans, responses were observed in 1/7 patients (14%) (1 PR). DCR (CR + PR + 6 SD) was 100%. Median time to response was 3.5 months. All 7 patients with disease control (PR or SD) continue on treatment in the trial.
Advanced 2L PD-L1 Negative Non-Small Cell Lung Cancer Patients (Stage IV, I-O Naïve)
Responses were observed in 3/4 patients (75%) (1 CR± and 2 PR). DCR (CR + PR) was 75%. Median time to response was 1.7 months. All 3 patients with responses continue on treatment in the trial.
Robust expansion of ICOS+ CD4 and CD8+ T cells in the blood and increased ICOS gene expression in the tumor were both observed with the combination of NKTR-214 and nivolumab.
The most common grade 1-2 adverse events were fatigue (74%), flu-like symptoms (68%), rash (60%) and pruritus (42%). There were no treatment discontinuations due to adverse events (AEs) or study deaths.
There were no grade 3 or higher immune-mediated AEs (such as colitis, dermatitis, hepatitis, pneumonitis or endocrinopathies) at the recommended Phase 2 dose or below
A recommended Phase 2 dose of NKTR-214 0.006 mg/kg q3w + nivolumab 360 mg q3w was established and is being evaluated in expansion cohorts in over 10 patient populations with melanoma, renal cell carcinoma, non-small cell lung cancer, bladder, and triple-negative breast cancers (n=~330).
Nektar and Bristol-Myers Squibb entered into a clinical collaboration in September of 2016 to evaluate the potential for the combination of Opdivo and NKTR-214 to show improved and sustained efficacy and tolerability above the current standard of care. Bristol-Myers Squibb and Nektar are equally sharing costs of the combined therapy trials. Nektar maintains its global commercial rights to NKTR-214.

NKTR-214 preferentially binds to the CD122 receptor on the surface of cancer-fighting immune cells in order to stimulate their proliferation. In clinical and preclinical studies, treatment with NKTR-214 resulted in expansion of these cells and mobilization into the tumor micro-environment.1,2,3 NKTR-214 has an antibody-like dosing regimen similar to the existing checkpoint inhibitor class of approved medicines.

◊ One patient with confirmed PR at last scan experienced an unconfirmed CR, there was one additional patient with unconfirmed PR in the melanoma cohort as of Nov 2, 2017.
+ Complete response is unconfirmed, patient has confirmed PR.

On November 10, 2017 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported that it is presenting two trials in progress posters summarizing study designs for ongoing clinical trials with MAGE-A4 and NY-ESO SPEAR T-cells at the 2017 SITC (Free SITC Whitepaper) annual meeting at the Gaylord National Hotel & Convention Center in National Harbor, Maryland, United States (Press release, Adaptimmune, NOV 10, 2017, View Source;p=RssLanding&cat=news&id=2316203 [SID1234521929]).

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Latest on SITC (Free SITC Whitepaper) through 1stOncology, book your free 1stOncology demo here.

Overview of Study Designs:

MAGE-A4 SPEAR T-cells targeting multiple solid tumors1:
– Open-label, non-randomized pilot study evaluating the safety, tolerability, and antitumor activity of MAGE-A4 SPEAR T-cells in patients with HLA-A*02 and MAGE-A4 positive inoperable locally advanced or metastatic tumor(s)
– This dose escalation study utilizes a modified 3+3 design:
• Group 1: to enroll 3-6 patients; dose of 100 million transduced SPEAR T-cells, 21-day interval for safety review
• Group 2: to enroll 3-6 patients; dose of 1 billion transduced SPEAR T-cells, 7-day interval for safety review2
• Group 3: to enroll 3-6 patients; dose of 1-5 billion transduced SPEAR T-cells, 7-day interval for safety review2
• Study allows for expansion at optimal dose range up to 20 patients across tumors
– Patients must be: ≥ 18 yrs old; HLA-A*02 positive; have MAGE-A4 positive inoperable locally advanced or metastatic tumor(s) at ≥1+ intensity in ≥ 10% of tumor cells MAGE-A4 expression by immunohistochemistry (IHC); have ECOG status 0 or 1; and adequate organ function
– Lymphodepletion regimen: fludarabine (30 mg/m2/day) and cyclophosphamide (600 mg/m2/day) for 3 days
– Efficacy assessed by overall response rate, time to response, duration of response, progression-free survival, and overall survival at weeks 4, 8, and 12, month 6, and then every 3 months until confirmation of disease progression
– The study is open and enrolling

NY‑ESO SPEAR T-cells with or without KEYTRUDA (pembrolizumab) in multiple myeloma:
– Open-label, randomized pilot study evaluating the safety, tolerability, and antitumor activity of NY-ESO SPEAR T-cells with or without KEYTRUDA in patients with multiple myeloma
– Eligible patients will be randomly assigned to a treatment arm: NY-ESO SPEAR T-cells alone (Arm 1) or NY-ESO-1 SPEAR T-cells in combination with KEYTRUDA (Arm 2)
– Target enrollment is 20 patients with 10 in each arm; eligible patients who do not receive the T‑cell infusion may be replaced.
– Patients must be: ≥ 18 yrs old; HLA-A*02:01, *02:05, or *02:06 positive; have histologically confirmed diagnosis of multiple myeloma with either primary refractory or relapsed/refractory disease expressing NY-ESO-1 and/or LAGE-1a; have received prior therapies including IMiD and a proteasome inhibitor as separate lines or a combined line of therapy; have ECOG status 0 or 1; and adequate organ function
– Lymphodepletion regimen: fludarabine (30 mg/m2/day) and cyclophosphamide (600 mg/m2/day) for 3 days, followed by granulocyte-colony stimulating factor
– For patients in Arm 2, KEYTRUDA will be administered every 3 weeks, starting at week 3 following T-cell infusion until week 108
– Target dose of 1 – 8 × 109 transduced SPEAR T-cells
– Efficacy will be assessed by the International Myeloma Working Group (IMWG) Uniform Response Criteria. Overall response rate, time to response, duration of response, progression-free survival, and overall survival will be determined.
– The study is open and enrolling

On November 10, 2017 Carna Biosciences reported that it has revised its consolidated results forecast for the fiscal year ending December 31, 2017 (Press release, Carna Biosciences, NOV 10, 2017, View Source [SID1234526522])

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(January 1, 2017 to December 31, 2017) announced on February 10, 2017.

1. Revised consolidated results forecast

Reason of the revision
Carna Biosciences has revised its full year consolidated sales forecast to 701 million yen. Sales forecast for the
Drug Discovery Support business was revised to 701 million yen from 1,000 million yen and sales forecast for
the Drug Discovery and Development business was revised to zero from 440 million yen.
At the Drug Discovery and Development business, we decided to revise our forecast because we concluded that
it would be difficult to receive the expected milestone payment of 440 million yen within this fiscal year for
SRA141 that Carna out-licensed to Sierra Oncology, Inc. Sierra is currently conducting preclinical research for
SRA141 as initially planned, aiming to expand its pipeline targeting DNA Damage Response (DDR). However,
given its near-term focus on broadening the development program for its lead asset SRA737, Sierra rescheduled
the development timeline of SRA141, and the IND submission has been postponed until next year. We decided
to revise our forecast, examining the current development status of SRA141 and other revenue from the Drug
Discovery and Development business.
At the Drug Discovery Support business, in order to achieve sales target of 1,000 million yen, we focused on the
marketing activity to win large scale contract for DGK assay kits from major pharmaceutical companies and
biotech companies mainly in North America. As a result of our efforts, such as providing DGK proteins and
smaller scale assay kits, we expect to receive medium scale orders within this fiscal year. However, we currently
expect that it would be difficult to achieve 220 million sales target for DGK assay kits and decided to revise our
sales forecast for North America to 238 million yen, down 48.9 % compared to the previous forecast and up
19.4% compared to the previous fiscal year. In Japan, sales from profiling services provided to Ono
Pharmaceutical are expected to fall short of the initial plan. As a result, we decided to revise sales forecast for
Japan to 366 million yen, down 14.1% compared to the previous forecast and down 12.5% compared to the
previous fiscal year. We also revised sales forecast for Europe to 70 million yen, down 16.8% compared to the
previous forecast and down 2.0% compared to the previous fiscal year and revised sales forecast for other region
to 26 million yen, up 18.5% compared to the previous forecast and up 19.6% compared to the previous fiscal year.
– 2 –
For operating income, we initially expected 39 million yen at consolidated level, 443 million yen from the Drug
Discovery Support business and loss of 403 million yen from the Drug Discovery and Development business.
However, after careful consideration, we decided to revise our consolidated operating profit forecast to operating
loss of 727 million yen. By segment, we now expect operating profit of 173 million yen for the Drug Discovery
Support business, down 270 million yen from the previous forecast, mainly due to a decline in gross profit caused
by the lower than expected sales. For the Drug Discovery and Development business, we now expect operating
loss of 901 million yen mainly due to a lack of milestone payment from Sierra.
As a result, we now expect ordinary loss of 738 million yen after considering non-operating income and expenses
and net loss attributable to owners of parent of 766 million yen.
We expect to receive milestone payment from Sierra in FY2018 since preclinical research of SRA141 is advancing
as expected. For DGK assay kits in North America, we plan to strengthen our marketing activity in an effort to
expand the expected medium scale contracts to large scale contract.
We plan to reduce unnecessary expenses thoroughly. At the same time, we continue to advance preclinical trials
and lead optimization of our compounds. We also aim to initiate in-house clinical trials and to out-license our
pipeline in order to maximize our corporate value.
* The forward-looking statements in this document have been prepared based on information available at the
time of the issuance of this release as well as on the certain assumptions considered by the management to be
reasonable. Actual results may differ from this forecast due to variety of factors.

On November 10, 2017 Alexo Therapeutics, a clinical-stage immuno-oncology company developing therapies that block the CD47 checkpoint mechanism exploited by cancer cells to evade the immune system, reported data from Alexo’s first-in-human Phase 1 study of its lead candidate, ALX148, at the Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper), being held in National Harbor, Maryland (Press release, Alexo Therapeutics, NOV 10, 2017, View Source [SID1234522016]). Preliminary results from the single agent portion of the trial (NCT03013218) showed that ALX148 is generally well tolerated in patients with advanced malignancy, with no dose-dependent impact on normal blood cells.

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"ALX148 is generally well tolerated and its clinical safety profile is consistent with that seen in our preclinical studies," said Sophia Randolph, M.D., Ph.D., Chief Medical Officer of Alexo. "Given the unique design of this high affinity CD47 blocker, we were able to achieve anticipated safety and pharmacokinetics, and complete CD47 target occupancy across the dosing interval. Having demonstrated single agent safety, we are encouraged to explore ALX148 in combination as a potential treatment option for cancer patients."

As of October 2017, ALX148 was intravenously administered as a single agent over a dose range of 0.3 mg/kg to 30 mg/kg in 17 patients with advanced malignancy. There was one treatment-related serious adverse event (neutropenia plus infection; 3.0 mg/kg) with no additional treatment-related events of neutropenia or infection of any grade reported. Most treatment-related adverse events were Grade 1 or 2 and occurred across eight patients, as sole events. Evaluation of the highest protocol defined dose level (30 mg/kg) is ongoing. Upon completion of the single agent portion, the second half of the trial will evaluate ALX148 in combination with checkpoint inhibitors and targeted anti-cancer antibodies.

About ALX148
ALX148 is a fusion protein that comprises an engineered high affinity CD47 binding domain of SIRPα linked to an inactive Fc region of human immunoglobulin. ALX148 potently and selectively binds CD47, blocking its interaction with SIRPα, thereby inhibiting a key immune checkpoint mechanism exploited by cancer cells. In preclinical studies, ALX148 enhances checkpoint inhibition by activating dendritic cells and reducing suppression by tumor-associated macrophages, and enhances targeted anti-cancer antibodies by maximizing phagocytosis to selectively eliminate tumor cells. ALX148 has demonstrated significant inhibition of tumor growth in these combinations with no adverse effect on CD47-expressing normal blood cells in preclinical models.

On November 10, 2017 Infinity Pharmaceuticals, Inc. (NASDAQ: INFI) reported Phase 1 clinical and translational data for IPI-549, an oral, selective phosphoinositide-3-kinase-gamma (PI3K-gamma) inhibitor that targets immune-suppressive tumor macrophages (Press release, Infinity Pharmaceuticals, NOV 10, 2017, View Source [SID1234521965]). These data from the recently completed monotherapy dose-escalation component of the Phase 1/1b study demonstrated that IPI-549 dosed once daily (QD) was well tolerated and clinically active. Among 18 patients evaluable for activity, there was a 44 percent clinical benefit rate, defined as patients who had remained on treatment for at least 16 weeks, including one partial response in a patient with advanced peritoneal mesothelioma. Additionally, initial translational data from patient blood samples demonstrated that IPI-549 treatment results in immune stimulation, with early evidence of biological activity correlating with clinical benefit. The late-breaking abstract describing these findings will be presented today in an oral presentation during the "Clinical Trials: New Agents" session at the 2017 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting taking place in National Harbor, MD, November 10 – 12. IPI-549 is believed to be the only selective PI3K-gamma inhibitor in clinical development.

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"As the majority of patients treated with IPI-549 monotherapy have advanced forms of cancer and received several therapies prior to enrollment in this study, it’s very encouraging that 44 percent of patients stayed on treatment for at least 16 weeks, including a patient with a partial response who has remained on treatment for over a year and continues on study today," stated David Hong, M.D., Deputy Chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. "There is a significant need for better treatment options for patients, especially for patients who do not respond to, or develop resistance to, existing immunotherapies as well as for types of cancer where there is limited benefit from treatment with checkpoint inhibitors. Selective inhibition of PI3K-gamma is emerging as an exciting new approach to inducing an immune response, and I look forward to my continued participation in this study."

Infinity is evaluating IPI-549 as a monotherapy and in combination with Opdivo (nivolumab), a PD-1 immune checkpoint inhibitor, in a Phase 1/1b study in approximately 200 patients with advanced solid tumors. The study includes four parts: monotherapy dose escalation, monotherapy expansion, combination dose escalation and combination expansion. Infinity has completed the monotherapy dose escalation, and the monotherapy expansion component of the study is underway. Infinity expects to complete the combination dose escalation and initiate the combination expansion cohorts by the end of 2017. To date, IPI-549 has been well tolerated as a monotherapy and in combination with Opdivo.

Infinity also announced today that it is adding two additional cohorts to the combination expansion component of the study, one in mesothelioma and one in adrenocortical carcinoma (cancer of the adrenal gland). These two new cohorts are based in part on the partial response reported in a patient with mesothelioma in the monotherapy dose-escalation portion of the study and a partial response in a patient with adrenocortical carcinoma in the combination dose-escalation component of the study. Both mesothelioma and adrenocortical carcinoma represent underserved patient populations.

"An important feature of our clinical trial is that it has a flexible design that allows us to continue to be data-driven in adding additional cohorts in response to evidence of clinical activity and medical need," stated Adelene Perkins, chief executive officer at Infinity. "In particular, patients with mesothelioma and adrenocortical carcinoma have limited effective treatment options, and our early evidence of activity suggest the potential for IPI-549 to improve outcomes for these patients."

"We are very pleased with how the Phase 1/1b study of IPI-549 continues to progress, and we anticipate additional results throughout 2018 from the monotherapy expansion cohort as well as data from the combination dose escalation and disease-specific expansion cohorts," Ms. Perkins continued.

Based on progress made during 2017, Infinity expects to achieve the following IPI-549 data milestones in 2018:

Report data from the monotherapy expansion component of the study in the first half of 2018
Report data from the combination dose-escalation component of the study in the first half of 2018
Report initial data from the combination expansion component of the study in the first half of 2018
Report additional data from at least six combination expansion cohorts, with more mature clinical and translational data, including insights from paired tumor biopsies, in the second half of 2018
Details of Today’s Late-Breaking Abstract

In an oral presentation entitled "Monotherapy dose escalation clinical and translational data from first-in-human study in advanced solid tumors of IPI-549, an oral, selective, PI3K-gamma inhibitor targeting tumor macrophages" (Abstract O43), Dr. Hong will discuss clinical and translational data from the monotherapy dose escalation of the Phase 1/1b study of IPI-549. The data reported today from an October 18, 2017, data cutoff included 19 patients evaluable for safety and 18 patients evaluable for activity who received monotherapy doses of IPI-549 ranging from 10 mg to 60 mg QD.

Summary of Clinical Data

Data from the monotherapy dose escalation demonstrated that IPI-549 treatment was well tolerated. Among 19 patients evaluable for safety, no dose limiting toxicities were identified, and a maximum tolerated dose was not reached. The majority of side effects reported were Grade 1 or Grade 2, and there were no treatment-related serious adverse events or deaths. The pharmacokinetic and pharmacodynamic properties of IPI-549 appeared favorable, with near-complete and sustained inhibition of PI3K-gamma at doses at or above 20 mg QD, supporting once daily dosing of IPI-549. Based on these findings, IPI-549 dosed at 60 mg QD was selected as the recommended monotherapy Phase 2 dose. The monotherapy expansion component of the study is currently ongoing.

Among 18 patients evaluable for activity, 44 percent (8 of 18 patients) showed a clinical benefit (defined as patients who remained on treatment for at least 16 weeks), including one partial response in a patient with advanced peritoneal mesothelioma who has remained on treatment for over one year.

Summary of Translational Data

Peripheral blood samples from patients treated with IPI-549 were analyzed to characterize the potential mechanism of immune response. Data showed that IPI-549 treatment resulted in immune stimulation, with upregulation of interferon-gamma responsive factors and reinvigoration of exhausted T cells across multiple tumor types and dose levels. Additionally, initial translational data showed clinical benefit was associated with increased numbers of immune-stimulated monocytes, suggesting a biologic correlate in patients who remained on treatment longer. Infinity is continuing its translational analyses and expects to report additional findings in 2018.

Infinity Investor/Analyst Reception and Webcast

In conjunction with the 2017 SITC (Free SITC Whitepaper) Annual Meeting, Infinity will host a reception and webcast for investors and analysts today, November 10, 2017, from 6:00 a.m. ET to 8:00 a.m. ET to discuss the clinical development of IPI-549, including a review of data from the Phase 1/1b clinical study. The presentation portion of the reception will be webcast beginning at 6:30 a.m. ET.

Featured speakers will include:

David Hong, M.D., Deputy Chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Taha Merghoub, Ph.D., Co-Director, Ludwig Collaborative Laboratory and the Swim Across America Laboratory at Memorial Sloan Kettering
The webcast and accompanying slides can be accessed in the "investors/media" section of the company’s website, www.infi.com. A replay of the event will also be available.

About the IPI-549 and the Ongoing Phase 1/1b Study

IPI-549 is an investigational, orally administered immuno-oncology development candidate that selectively inhibits PI3K-gamma. In preclinical studies, IPI-549 reprograms macrophages from a pro-tumor, M2, to an anti-tumor, M1, phenotype and is able to overcome resistance to checkpoint inhibition as well as to enhance the activity of checkpoint inhibitors.1,2 As such, IPI-549 may have the potential to treat a broad range of solid tumors and represents a potentially additive or synergistic approach to restoring anti-tumor immunity in combination with other immunotherapies such as checkpoint inhibitors.

The ongoing Phase 1/1b study being conducted by Infinity is designed to evaluate the safety, tolerability, activity, pharmacokinetics and pharmacodynamics of IPI-549 as a monotherapy and in combination with Opdivo in approximately 200 patients with advanced solid tumors.3 The four-part study includes monotherapy and combination dose-escalation components, in addition to monotherapy expansion and combination expansion components. Patient enrollment is complete in monotherapy dose-escalation, and monotherapy expansion is ongoing. Combination dose-escalation is also ongoing, and combination expansion is expected to begin this year.

The combination expansion component of the study includes multiple cohorts designed to evaluate IPI-549 in patients with specific types of cancer, including patients with non-small cell lung cancer (NSCLC), melanoma, and head and neck squamous cell carcinoma (HNSCC) whose tumors show initial resistance or initially respond to but subsequently develop resistance to immune checkpoint blockade therapy. The combination expansion component also includes a cohort of patients with triple negative breast cancer (TNBC) who have not been previously treated with immune checkpoint blockade therapy, a cohort of patients with mesothelioma and a cohort of patients with adrenocortical carcinoma.

IPI-549 is an investigational compound and its safety and efficacy has not been evaluated by the U.S. Food and Drug Administration or any other health authority.