On November 13, 2017 Novartis reported that it has had a strong year in innovation with several key approvals and positive trial readouts (Press release, Novartis, NOV 12, 2017, View Source [SID1234521950]). Novartis holds an R&D and investor update in London, which will provide deeper insights into key late-stage pipeline projects. In the Oncology business unit, Novartis is pursuing multiple indications for Kymriah, the first-in-class CAR-T therapy, and could further strengthen the oncology pipeline if the proposed acquisition of Advanced Accelerator Applications is closed. In the Pharmaceuticals business unit, Novartis continues to strengthen its position in Multiple Sclerosis through BAF312 (siponimod), OMB157 (ofatumumab) and the recent pediatric findings for Gilenya. During the investor event Novartis will provide a deep dive on the four selected programs below.

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In Ophthalmology, RTH258 (brolucizumab) data presented at the American Academy of Ophthalmology showed superiority versus aflibercept in key secondary endpoints reflective of disease activity in patients with nAMD. Patients treated with RTH258 showed fewer signs of specific disease activity than patients treated with aflibercept. RTH258 patients showed less retinal fluids, less fluid in the deepest part of the retina and superior reductions in retinal thickness. Novartis expects to file for the nAMD indication by Q4 2018 and expects to start clinical trials in DME and RVO during 2018. Additionally, RTH258 creates the potential opportunity for Novartis to enter the attractive growing US retina market.

In Neuroscience, AMG 334 (erenumab) is being developed to deliver an effective and safe prophylactic treatment for patients suffering from chronic or episodic migraine. This debilitating disease affects more than 10% of adults, mainly in their prime working years. AMG 334 has shown encouraging results in reducing monthly migraine days, even in difficult to treat patients. AMG 334 is a fully human, potent, selective CGRP antagonist targeting the receptor and it was the first CGRP antagonist to be filed in the US and EU, on track for a potential first-in-class launch in 2018.

In Immunology, Cosentyx continues to build on its best-in-class profile, which has demonstrated sustained control of signs and symptoms in PSO, PsA and AS. Cosentyx has strong differentiation based on its unique biology which has shown a high level of enthesitis resolution and no radiographic progression in psoriatic arthritis and ankylosing spondylitis. By targeting the IL-17A pathway, the cornerstone cytokine of enthesitis, Cosentyx has the potential to change the course of disease in AS and PsA. Cosentyx is uniquely positioned to continue growth in all indications, particularly in spondyloarthritis, where the segment opportunity is larger than psoriasis.

In Cardiology, ACZ885 (canakinumab) data showed there was a significant reduction in major adverse cardiac events, in a subpopulation of patients who achieved hsCRP<2mg/L three months after the initial treatment. This well defined target population is critical to establishing the product’s value proposition and commercial uptake. Feedback from FDA and EU regulators supports moving forward with regulatory submissions for cardiovascular risk reduction, which are planned for Q4 and onwards. The novelty of approach to reduce CV risk is recognized by the regulators and there is interest in understanding the relationship between hsCRP and patient response.

For background slides and webcast (audio only) please refer to the following link: View Source
The background slide decks will be available on Monday November 13th, 2017.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "pipeline," "on track," "moving forward," "will," "pursuing," "could," "continues," "expects," "by Q4 2018," "during 2018," "potential," "growing," "being developed," "encouraging," "launch," "to build," "positioned," "opportunity," "planned," "for Q4 and onwards," "interest in," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational and approved products described in this press release, including RTH258, AMG 334, ACZ885, BAF312, OMB157, Cosentyx, Kymriah and Gilenya, or regarding potential future revenues from such investigational and approved products, or by express or implied discussions regarding the potential outcome of the tender offer for Advanced Accelerator Applications, and the potential impact on Novartis of the proposed acquisition, including express or implied discussions regarding potential future sales or earnings of Novartis, and any potential strategic benefits, synergies or opportunities expected as a result of the proposed acquisition. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that any new products will be approved for sale in any market, or that any new indications will be approved for any existing products in any market, or that any approvals which are obtained will be obtained at any particular time, or that any such products will achieve any particular revenue levels. Neither can there be any guarantee that the investigational or approved products described in this press release will be commercially successful in the future. Nor can there be any guarantee that the proposed acquisition described in this press release will be completed, or that it will be completed as currently proposed, or at any particular time. Neither can there be any guarantee that Novartis will achieve any particular future financial results as a result of the proposed acquisition, or that Novartis will be able to realize any potential strategic benefits, synergies or opportunities as a result of the proposed acquisition. Nor can there be any guarantee that shareholders will achieve any particular level of shareholder returns. Neither can there be any guarantee that the Group, or any of its divisions, will be commercially successful in the future, or achieve any particular credit rating or financial results. In particular, our expectations could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally, including potential regulatory actions or delays relating to the completion of the potential acquisition described in this press release, as well as potential regulatory actions or delays with respect to the development of the products described in this press release; the potential that the strategic benefits, synergies or opportunities expected from the proposed acquisition may not be realized or may take longer to realize than expected; uncertainties regarding actual or potential legal proceedings, including, among others, potential legal proceedings with respect to the proposed acquisition; our ability to obtain or maintain proprietary intellectual property protection, including the ultimate extent of the impact on Novartis of the loss of patent protection and exclusivity on key products which commenced in prior years and will continue this year; the particular prescribing preferences of physicians and patients; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures, such as from increased publicity on pharmaceuticals pricing, including in certain large markets; general economic and industry conditions, including the effects of the persistently weak economic and financial environment in many countries; uncertainties regarding future demand for our products; safety, quality or manufacturing issues, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

Additional Information
Novartis announced October 30, 2017, that it had entered a memorandum of understanding with Advanced Accelerator Applications (AAA) under which Novartis intends to commence a tender offer for 100% of the share capital of AAA. The transaction is subject to certain closing conditions. Novartis will commence a tender offer upon completion of works council consultation and AAA’s Board of Directors recommending the tender offer to AAA shareholders. The senior management and Directors of AAA have, in their capacity as shareholders of AAA, undertaken to tender their shares into the proposed tender offer. The transaction is additionally subject to (i) the valid tender pursuant to the tender offer of ordinary shares (including ordinary shares in the form of American Depositary Shares) of AAA representing at least 80% of the outstanding ordinary shares on a fully diluted basis and (ii) receipt of customary transactional regulatory approvals and other customary closing conditions. Until such time as the closing conditions are satisfied, Lutathera remains under the custody and control of AAA. Novartis does not currently own or control these projects and will not have the ability to influence them until closing of the proposed acquisition of AAA which is subject to certain closing conditions and regulatory approvals.

Lutathera is a registered trademark of Advanced Accelerator Applications.

On November 13, 2017 argenx (Euronext & Nasdaq: ARGX) a clinical-stage biotechnology company developing a deep pipeline of differentiated antibody-based therapies for the treatment of severe autoimmune diseases and cancer, reported that management will present at several upcoming investor conferences in November (Press release, argenx, NOV 12, 2017, View Source;p=RssLanding&cat=news&id=2316341 [SID1234521948]):

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Stifel 2017 Healthcare Conference. Chief Scientific Officer, Hans de Haard, will present on Wednesday, November 15, 2017 at 2:45 p.m. ET in New York City.
Jefferies 2017 London Healthcare Conference. Chief Executive Officer, Tim Van Hauwermeiren, will present on Thursday, November 16, 2017 at 11:20 a.m. UTC in London.
Piper Jaffray 29th Annual Healthcare Conference. Chief Executive Officer, Tim Van Hauwermeiren, will present on Wednesday, November 29, 2017 at 2:30 p.m. ET in New York City.
Live webcasts of the presentations will be available on the Company’s website at www.argenx.com. Replays of the webcasts will be availalbe for 90 days following the presentation.

Phase I, First-in-Human, Open-Label, Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Activity of M4112 an IDO1/TDO2 Inhibitor as Single Agent and Sequentially in Combinations with Avelumab or M7824 (TGFß Trap) in Subjects with Metastatic or Locally Advanced Unresectable Solid Tumors

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There are 2 parts to this study: Part 1 and Part 2. This consent form is for Part 1 only. In Part 1, there are 3 sub-groups: Part 1A, 1B, and 1C. The goal of this clinical research study is to find the highest tolerable dose of M4112 that can be given to patients with advanced or metastatic (have spread) solid tumors that are unresectable (cannot be removed with surgery). In this study, M4112 will be studied alone (Part 1A) or in combination with either avelumab (Part 1B) or M7824 (Part 1C). This is the first study using M4112 in humans. The safety of M4112 and the drug combinations will also be studied.

General Information

Disease Group: Malignant neoplasms of ill-defined secondary and unspecified sites,Malignant neoplasms of independent (primary) multiple sites

Treatment Agent: Avelumab,M4112,MSB0011359C

Treatment Location: Both at MDACC & and Other Sites

Sponsor: EMD Serono

Study Objectives/Outcome

Primary Objectives Part IA (Dose Escalation – M4112 as Single Agent) To determine safety and tolerability or, if observed, the maximum tolerated dose (MTD), and to define the recommended phase 2 dose (RP2D) of M4112 as single agent in subjects with solid tumors. Part IB (Dose Escalation – M4112 in Combination with Avelumab) To determine safety and tolerability or, if observed, the MTD, and to define the RP2D of M4112 in combination with avelumab in subjects with solid tumors. Part IC (Dose Escalation – M4112 in Combination with M7824) To determine safety and tolerability or, if observed, the MTD, and to define the RP2D of M4112 in combination with M7824 in subjects with solid tumors. Secondary Objectives Part IA (Dose Escalation – M4112 as Single Agent) To characterize the pharmacokinetic (PK) parameters of M4112 as single agent. To assess QT prolongation potential by central tendency, outlier analysis and the slope of exposure-QT corrected interval (QTc) analysis to evaluate preliminary clinical activity parameters using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. To evaluate preliminary clinical activity parameters using RECIST 1.1. Part IB (Dose Escalation – M4112 in Combination with Avelumab) To characterize the PK parameters of M4112 and avelumab exposure in combination. To evaluate the immunogenicity of avelumab when given in combination with M4112. To evaluate preliminary clinical activity parameters using RECIST 1.1. Part IC (Dose Escalation – M4112 in Combination with M7824) To characterize the PK parameters of M4112 and M7824 exposure in combination. To evaluate the immunogenicity of M7824 when given in combination with M4112. To evaluate preliminary clinical activity parameters using RECIST 1.1. Exploratory Objectives Part IA (Dose Escalation – M4112 as Single Agent) To evaluate the effect of M4112 on kynurenine (Kyn) and tryptophan (Trp) in plasma of subjects. To evaluate the effect of M4112 on indoleamine-2,3-dioxygenase 1 (IDO1) activity in ex vivo stimulated whole blood of subjects. To study genetic variations that may affect the safety and tolerability, PK and pharmacodynamics (PD) profiles of M4112. To evaluate the effects of M4112 on changes in immune phenotype and cytokines in relation to treatment-related adverse events (TRAE) and clinical outcomes. To assess effects of M4112 as single agent on 4B-hydroxycholesterol and cholesterol activity. Part IB (Dose Escalation – M4112 in Combination with Avelumab) To evaluate the effect of M4112 in combination with avelumab on Kyn and Trp in plasma of subjects. To evaluate the effect of M4112 on IDO1 activity in ex vivo stimulated whole blood of subjects. To study genetic variations that may affect the safety and tolerability, PK and PD profiles of M4112 in combination with avelumab. To evaluate the effects of M4112 in combination with avelumab on changes in immune phenotype and cytokines in relation to TRAE and clinical outcomes. Part IC (Dose Escalation – M4112 in Combination with M7824) To evaluate the effect of M4112 in combination with M7824 on Kyn and Trp in plasma of subjects. To evaluate the effect of M4112 on IDO1 activity in ex vivo stimulated whole blood of subjects. To study genetic variations that may affect the safety and tolerability, PK and PD profiles of M4112 in combination with M7824. To evaluate the effects of M4112 in combination with M7824 on changes in immune phenotype and cytokines in relation to TRAE and clinical outcomes.

IRB Review and Approval Date: 12/11/2017

Recruitment Status: Open

Projected Accrual: 60

Enrollment Eligibility
Eligibility:

1) Signed written informed consent form (ICF) before any study-related procedure is undertaken that is not part of the standard subject management.
2) Male or female subjects >/= 18 years of age.
3) Subject population: a. In the dose escalation cohorts (Part IA to Part IC): Histologically or cytologically proven advanced or metastatic solid malignancies for whom no effective standard therapy exists or has failed or subjects who are intolerant to established therapy known to provide clinical benefit for their condition.
4) Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at Screening.
5) Subjects who have been treated previously with a checkpoint inhibitor may enroll.
6) Adequate hematological function as defined below: a. Absolute neutrophil count >/= 1,500/mm^3 or >/= 1.5 × 10^9/L; b. Platelet count >/= 100,000/mm^3 or >/= 100 × 10^9/L; c. Hemoglobin >/= 9 g/dL.
7) Adequate hepatic function defined: by a total bilirubin level 1.5 × ULN but < 3 × ULN; b. Subjects with tumor involvement in their liver: AST < 3.0 × ULN, ALT < 3.0 × ULN, with normal bilirubin 8) Adequate renal function defined by an estimated glomerular filtration rate > 50 mL/min according to the Cockcroft-Gault formula or normal creatinine laboratory values. (Glomerular filtration rate [mL/min/1.73 m^2] = 175 × serum creatinine (Scr)-1.154 × age – 0.203 × 1.212 [if African American] × 0.742 [if female]).
9) Male participants must agree to use and to have their female partners use a highly effective contraception (i.e., methods with a failure rate of less than 1 % per year) as detailed in protocol 30 days before first dose of study treatment (as appropriate), during the treatment period and for at least 60 days after the last dose of study treatment of M4112 as single agent or in combination with avelumab and for at least 120 days after the last dose of M7824 and must refrain from donating sperm during this period.
10) Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) as defined in protocol, OR b. A WOCBP who agrees to use a highly effective contraception (i.e., methods with a failure rate of less than 1 % per year) as detailed in protocol 30 days before start of first dose of study treatment (as appropriate), during the treatment period and for at least 60 days after the last dose of study treatment of M4112 as single agent or in combination with avelumab and for at least 120 days after the last dose of M7824. Since the effect of potential of M4112 to induce/inhibit CYP3A4 is unknown at this time, WOCBP that are currently using hormonal contraception that is a substrate for CYP3A4 should also use double barrier contraception.
11) Women of childbearing potential must have a negative plasma pregnancy test at the Screening Visit and a negative urine pregnancy test on Day 1 before enrollment and dosing.
Exclusion:

1) Prior therapy with: In combination with avelumab or M7824 in the dose escalation only cohorts (Part 1B and Part 1C): Intolerance to immune checkpoint inhibitor therapy as defined by the occurrence of an adverse drug reaction (ADR) requiring drug discontinuation.
2) Persisting toxicity related to prior therapy Grade > 1 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 4.03, however sensory neuropathy Grade 3) Prior organ transplantation including allogeneic stem cell transplantation.
4) All subjects with known brain metastases, except those meeting the following criteria: a. Brain metastases that have been treated locally and are clinically stable for at least 4 weeks prior to the start of treatment. b. No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable). c. Subjects must be either off steroids or on a stable or decreasing dose of < 10 mg daily prednisone (or equivalent).
5) Concurrent treatment with a non-permitted drug/intervention: a. Strong inhibitors or inducers of CYP3A4, and drugs with a narrow therapeutic index, which are predominantly metabolized by CYP3A4 should be discontinued 7 days prior to treatment and avoided during treatment. b. Drugs known to have a high risk of prolonging QTc as per label. c. Drugs that are known to increase gastric pH should be stopped at least 1 week before the start of study treatment.
6) Continued from #5: d. Anticancer treatment (eg, cytoreductive therapy, radiotherapy, immune therapy, cytokine therapy, monoclonal antibody, targeted small molecule therapy) or any investigational drug within 4 weeks prior to start of study treatment, or not recovered from adverse event (AE) related to such therapies, with the following exceptions: i. Palliative bone-directed radiotherapy is permitted (concurrently or within pretreatment period). ii. Hormonal therapies acting on the hypothalamic-pituitary-gonadal axis are permitted (ie, luteinizing hormone-releasing hormone agonist/antagonists). No other hormonal anticancer therapy is permitted. e. Major surgery (as deemed by the Investigator) for any reason, except diagnostic biopsy, within 4 weeks of the study treatment and/or if the subject has not fully recovered from the surgery within 4 weeks of the study treatment.
7) Continued from #5: f. Subjects receiving immunosuppressive agents (such as steroids), for any reason, should be tapered off these drugs before start of study treatment, with the following exceptions: i. Subjects with adrenal insufficiency, may continue corticosteroids at physiologic replacement dose, equivalent to < 10 mg prednisone daily. ii. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation). iii. Previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon is acceptable as long as it is anticipated that the administration of steroids will be completed in 14 days, or that the dose after 14 days will be equivalent to 8) Current significant cardiac conduction abnormalities, including corrected QT interval (QTc) prolongation of > 450 milliseconds or impaired cardiovascular function, ventricular tachycardia, hypokalemia or a history of paroxysmal atrial fibrillation, serious cardiac arrhythmia and family history of sudden death or long QT syndrome.
9) A history of cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina or congestive heart failure (New York Heart Association Classification Class >/= II).
10) Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: a. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible. b. Autoimmune diseases: eg, inflammatory bowel diseases, interstitial lung disease or pulmonary fibrosis.
11) Pneumonitis and history of pneumonitis.
12) A history of difficulty of swallowing, gastric or small bowel surgery with history of malabsorption or other chronic gastro-intestinal disease or conditions that may hamper compliance and/or absorption of the M4112.
13) Any psychiatric condition that would prohibit the understanding or rendering of Informed Consent, or interfere with compliance to study requirements and procedures in the opinion of Investigator and/or Sponsor.
14) Known current alcohol and drug abuse as determined by the Investigator if no consent by legal representative.
15) Hepatocellular carcinoma.
16) Legal incapacity or limited legal capacity.
17) Significant acute or chronic infections requiring systemic therapy including, among others: a. History of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. b. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as, HBV surface antigen positive and HBV core antibody positive with reflex to positive HBV DNA or HBV core antibody positive alone with reflex to positive HBV DNA or positive HCV antibody with reflex to positive HCV RNA). Subjects with a history of infection must have polymerase chain reaction documentation that infection has cleared. c. Active tuberculosis (history of exposure or history of positive TB test with presence of clinical symptoms, physical, or radiographic findings).
18) Known hypersensitivity to the investigational medicinal products (IMPs) or to one or more of the excipients of M4112, avelumab or M7824.
19) Known severe hypersensitivity reactions to monoclonal antibodies (Grade >/= 3 NCI-CTCAE 4.03), or uncontrolled asthma (ie, 3 or more features of partially controlled asthma).
20) Pregnancy or lactation.
21) Administration of a live vaccine within 28 days prior to study entry.
For Enrollment:

713-563-1930

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 11, 2017 Argos Therapeutics, Inc. (NASDAQ:ARGS), an immuno-oncology company focused on the development and commercialization of individualized immunotherapies based on the Arcelis precision immunotherapy technology platform, reported an update on the immunology data from the February 2017 interim analysis of data from the ongoing Phase 3 ADAPT clinical trial evaluating Rocapuldencel-T for the treatment of metastatic renal cell carcinoma (mRCC) presented in the poster session at the 32nd Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) in National Harbor, Maryland(Press release, Argos Therapeutics, NOV 11, 2017, View Source [SID1234521943]). The presentation is focused primarily upon immunology data from the ADAPT clinical trial and includes both new data and an update to data that was previously presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Conference in September 2017 that now includes additional patients.

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As background, a total of 462 patients were enrolled in the ADAPT study and randomized 2:1 between combination treatment with Rocapuldencel-T and sunitinib (combination arm) vs. sunitinib monotherapy (control arm).

Immunology data from the February 2017 interim analysis of the data from the ADAPT study reported at the SITC (Free SITC Whitepaper) Conference were pre-specified and include correlations between survival and (i) the change from baseline in antigen-specific memory T-cells, (ii) the amount of IL-12 secreted by each patient’s specific Rocapuldencel-T immunotherapy, and (iii) the percentage of regulatory T-cells at baseline, which was observed in both arms of the study. Of note, data for antigen-specific memory T-cells and regulatory T-cells were available only for patients enrolled at North American sites.

Increase from Baseline in Antigen-Specific Memory T-Cells

In subjects for whom immune response data were analyzed (n=146), the number of antigen-specific memory T-cells was found to increase only after administration of Rocapuldencel-T. In those subjects who received at least seven doses of Rocapuldencel-T (n=100), the average number of antigen-specific memory T-cells after the seventh dose was approximately double the number observed before treatment. This increase was found to be statistically significant (p<0.0001). Similar data on a smaller number of patients were presented at the European Society for Medical Oncology Conference in September 2017.

Additionally, for those subjects who received at least seven doses of Rocapuldencel-T, there was a statistically significant correlation between survival and the change in the number of antigen-specific memory T-cells from baseline (Spearman’s Rho = 0.40; p<0.0001). For those 25 patients with the greatest increase in the number of antigen-specific memory T-cells from baseline, no patient deaths had been recorded as of the time of the February 2017 interim analysis.

IL-12 Secretion by Each Patient’s Specific Rocapuldencel-T Immunotherapy

An analysis was conducted to evaluate the relationship between the amount of IL-12 secreted by each patient’s specific immunotherapy and that patient’s survival. Samples from patients treated with Rocapuldencel-T as of February 2017 (n=179) were divided into two groups: those with above the median amount of IL-12, and those with below the median amount of IL-12. Comparison of the Kaplan-Meier curves for these two groups revealed that those with higher than median levels of IL-12 demonstrated improved survival. Additionally, there was a statistically significant correlation between the level of IL-12 and survival (Spearman’s Rho = 0.27; p<0.0002). There was also a statistically significant correlation between the level of IL-12 and the change from baseline in antigen-specific memory T-cells for patients who received at least seven doses of Rocapuldencel-T (n=95; Spearman’s Rho = 0.43; p<0.0001).

Regulatory T-Cells

An analysis was conducted to evaluate the relationship between the percentage of regulatory T-cells at baseline and survival for patients in both arms of the trial. Samples from patients in the combination arm (n=176) were divided into two groups: those with above median percentage of regulatory T-cells at baseline, and those with below median percentage of regulatory T-cells at baseline. Comparison of the Kaplan-Meier curves for these two groups revealed that those with higher than median percentage of regulatory T-cells at baseline demonstrated improved survival. This finding was in contrast to the control arm (n=79), where a greater percentage of regulatory T-cells at baseline was associated with poorer survival. One hypothesis that could potentially explain this result is that Rocapuldencel-T may be acting to convert regulatory T-cells to effector T-cells.

Commenting on the additional immunology data, Charles Nicolette, Chief Scientific Officer of Argos Therapeutics, noted, "As we have conducted additional analyses of the immunology data from the February 2017 interim analysis, we have been pleased to see that the data are generally supportive of our hypothesis regarding the intended mechanism of action of Rocapuldencel-T to induce an immune response against the tumor in patients with metastatic renal cell carcinoma. While we await further data from the next planned interim data analysis that we expect to be conducted during the first half of 2018, pending agreement with the FDA on a revised protocol that we plan to submit, we are encouraged to see these positive indicators of activity."

As previously reported, the February 2017 interim analysis was conducted by the ADAPT trial’s Independent Data Monitoring Committee (IDMC) after 75% of the originally targeted number of 290 events (deaths) for the analysis of the primary endpoint of overall survival had occurred. At the time of the analysis, with more than half of the patients still alive in each arm and a median follow-up time of ~20 months, the IDMC concluded that the trial was unlikely to demonstrate a statistically significant improvement in median overall survival in the combination arm and recommended that the trial be discontinued for futility. However, the ADAPT trial principal investigators and Argos considered the data too immature to observe the delayed effects typically associated with immunotherapy and decided to continue the trial pending further review and analysis of the data and discussions with the U.S. Food and Drug Administration (FDA). In making this determination, Argos considered, among other factors, the degree of maturity of the data set, the mechanism of action of Rocapuldencel-T, which involves the induction of a long-term memory immune response, and the IDMC’s assessment of the safety profile of Rocapuldencel-T. This determination was subsequently further supported by the extended durability of tumor responses in the combination arm, as previously reported.

Following the IDMC’s interim analysis, the Company met with the FDA to discuss the ADAPT trial and the future direction of the Rocapuldencel-T program in April 2017. The FDA agreed with the Company’s decision to continue the ADAPT trial, and further agreed to review a protocol amendment to extend the trial beyond the originally targeted 290 events and a revised statistical analysis plan that the Company plans to submit.

Conference Call Information

Argos will hold a conference call to discuss the data presented at the 32nd Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) on Monday, November 13th at 8:30am ET. To participate by telephone, please dial (855) 433-0930 (Domestic) or (484) 756-4271 (International). The conference ID number is 9396519. Slides setting forth the data presented at the SITC (Free SITC Whitepaper) 2017 Annual Meeting, and a live and archived audio webcast, will be accessible through the Investors section of the Company’s website at www.argostherapeutics.com. The archived webcast will remain available on the Company’s website for twelve (12) months following the call.