Cyclacel has filed a 10-Q – Quarterly report [Sections 13 or 15(d)] with the U.S. Securities and Exchange Commission (Filing, 10-Q, Cyclacel, 2017, NOV 13, 2017, View Source [SID1234521992]).

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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.

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 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.

On November 11, 2017 Corvus Pharmaceuticals, Inc. (NASDAQ:CRVS), a clinical-stage biopharmaceutical company focused on the development and commercialization of novel immuno-oncology therapies, reported updated clinical data from the renal cell carcinoma (RCC) expansion cohorts of its ongoing Phase 1/1b study of CPI-444 as a single agent and in combination with atezolizumab (TECENTRIQ) (Press release, Corvus Pharmaceuticals, NOV 11, 2017, View Source;p=RssLanding&cat=news&id=2316328 [SID1234521944]). Results showed a response rate of 14 percent (two partial responses, one of which was unconfirmed) with single agent CPI-444 and 13 percent (two confirmed partial responses) for the combination therapy, and a disease control rate of 29 percent and 69 percent for single agent and combination therapy, respectively, in 30 response-evaluable patients. Additionally, biomarker data from the trial showed an association between adenosine pathway gene expression and response to therapy, and resistance to prior anti-PD-(L)1 treatment. The clinical and biomarker data were presented today in an oral session at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 32ND Annual Meeting in National Harbor, Md., by Jason J. Luke, M.D., a medical oncologist and assistant professor of medicine at the University of Chicago Medicine.

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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).

"These data provide new information on the importance of the adenosine pathway and its value as a target for cancer immunotherapy," said Dr. Luke. "We are seeing clinical activity in patients with RCC and other tumors, including patients who are resistant to prior anti-PD-(L)1 therapy and have few treatment options. The early biomarker data show that prior exposure to anti-PD-(L)1 increases expression of adenosine pathway genes, supporting earlier research indicating that the adenosine pathway is a resistance mechanism to anti-PD-(L)1 therapy. The data suggest that it may be possible to use biomarkers, specifically tumor expression of the A2A receptor and CD73, to identify patients with RCC and other tumors who are most likely to respond to treatment with CPI-444 or other forms of adenosine blockade."

The ongoing Phase 1/1b clinical trial has enrolled more than 225 patients with several tumor types including RCC, non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), melanoma and other tumors. To date, RCC (single agent and combination) and NSCLC (single agent and combination) cohorts have met the protocol-defined criteria for expansion from 14 to 26 patients. For both the RCC single agent and combination cohorts, criteria for expansion to 48 patients per cohort have been reached. Of 51 patients with RCC enrolled in the study, 69 percent were resistant or refractory to prior anti-PD-(L)1 therapy, having failed those therapies within a median time of 1.6 months prior to enrollment. The RCC patients had several adverse prognostic features including visceral metastases (88 percent), hepatic metastases (20 percent), anemia (45 percent) and elevated serum lactate dehydrogenase (21 percent).

"Our Phase 1/1b study continues to generate important clinical and biologic data that is helping us identify mechanisms of resistance to anti-PD-(L)1 therapies. With that data, we may be able to identify clinical characteristics and biomarkers associated with a clinical response, optimize treatment regimens and improve patient outcomes," said Richard A. Miller, an oncologist and co-founder, president and chief executive officer of Corvus. "In 2018, we anticipate initiating a pivotal trial of CPI-444 in RCC and, utilizing the information we have learned to date, selecting patients most likely to benefit from treatment. We also intend to initiate a clinical trial of our anti-CD73 antibody in the first half of 2018, which is another approach to blockade of the adenosine pathway in RCC and other cancers."

KEY CLINICAL RESULTS PRESENTED AT SITC (Free SITC Whitepaper)
Updated efficacy and safety data from the single agent and combination RCC cohorts were presented at SITC (Free SITC Whitepaper). 51 patients with RCC have been enrolled to date. Data from 14 patients receiving CPI-444 single agent therapy and 16 receiving combination therapy who were evaluable for response showed:

Four patients experienced a partial response (one confirmed and one unconfirmed with single agent therapy and two confirmed partial responses with combination). Both single agent responses occurred in patients resistant or refractory to prior treatment with anti-PD-(L)1.
Disease control (stable disease and partial responses) was achieved in 29 percent and 69 percent of patients receiving single agent and combination therapy, respectively.
CPI-444 continues to be well tolerated to date, with observed adverse events similar to previous reports. In both the single-agent and combination arms for the entire safety data set (N=210), Grade 1 and 2 adverse events occurring in 5 or more percent of patients included fatigue, nausea, pruritis, pyrexia, decreased appetite, diarrhea and anemia. One patient had Grade 3 nausea, vomiting and diarrhea in the single agent arm. Four patients had a serious Grade 3 toxicity in the combination arm, one with hepatitis, one with pneumonitis, one with hemolytic anemia, and one with hepatitis, mucositis, pneumonitis and dermatitis. One other patient in the combination arm had both Grade 4 encephalitis and Grade 3 thrombocytopenia.
KEY BIOMARKER RESULTS PRESENTED AT SITC (Free SITC Whitepaper)
Biomarker analysis, performed on blood and tumor tissues from the RCC and NSCLC cohorts, showed:

Tumor expression of the A2A receptor, CD73 and CD39 was increased in patients resistant to prior treatment with anti-PD-(L)1.
Patients with RCC and NSCLC had high tumor expression of the A2A receptor, CD73 and CD39 in screening, pre-treatment biopsies compared to patients with other tumors.
Biopsies showed that treatment with CPI-444 increased CD8 positive cell infiltration in tumors and induced expression of genes consistent with Th1 activation.
For patients enrolled in the study with all tumor histologies and for whom screening biopsies were available for analysis, tumor expression of the A2A receptor and CD73 was associated with a response to CPI-444, as follows:

Patients with high expression of the A2A receptor had a disease control rate of 29 percent (10 of 34) compared with 10 percent (four of 39) for those with low expression.
Patients with high expression of CD73 had a disease control rate of 24 percent (12 of 51) compared with 9 percent (two of 22) for those with low expression.
Patients with high expression of both the A2A receptor and CD73, referred to as double positive, had a disease control rate of 42 percent (10 of 24) compared to 8 percent for those without double positive tumors (four of 47), p<0.0007.
All four of the patients with a partial response were double positive (two RCC patients, one NSCLC patient and one MSI-H colon cancer patient). Tissue was not available for all patients with a partial response.
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, 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.

ABOUT CPI-444
CPI-444 is a small molecule, oral, checkpoint inhibitor designed to disable a tumor’s ability to subvert attack by the immune system by blocking the binding of adenosine in the tumor microenvironment to the A2A receptor. Adenosine, a metabolite of ATP (adenosine tri-phosphate), is produced within the tumor microenvironment where it may bind to the adenosine A2A receptor present on immune cells and block their activity. CD39 and CD73 are enzymes on the surface of tumor cells and immune cells. These enzymes work in concert to convert ATP to adenosine.