This is an open label, dose escalation phase I study to evaluate the clinical safety, tolerability in subjects with advanced solid tumors, and to establish the Maximum Tolerated Dose (MTD#, if any). This study is composed of two dose level: 1 and 3 mg/kg.

Start Date27 Dec 2019

Sponsor / Collaborator

Cornerstone Pharmaceutical Co., Ltd

CTR20192396 / CompletedPhase 1

一项评估抗CTLA-4 抗体CS1002 治疗晚期实体瘤患者的开放、剂量递增I 期临床研究

[Translation] An open-label, dose-escalation Phase I clinical study evaluating the anti-CTLA-4 antibody CS1002 in patients with advanced solid tumors

评估CS1002 在晚期/转移性实体瘤受试者中的安全性与耐受性；确定最大耐受剂量（MTD，如存在）；描述CS1002 的药代动力学（PK）特征；评估CS1002 的初步抗肿瘤活性；评估CS1002 的免疫原性。

[Translation]

To evaluate the safety and tolerability of CS1002 in subjects with advanced/metastatic solid tumors; to determine the maximum tolerated dose (MTD, if any); to characterize the pharmacokinetic (PK) properties of CS1002; to evaluate the preliminary antitumor activity of CS1002; and to evaluate the immunogenicity of CS1002.

Start Date27 Dec 2019

Sponsor / Collaborator

Cstone Pharmaceutical (Shanghai) Co Ltd

[+1]

NCT03523819 / CompletedPhase 1

A Phase Ia/Ib, Open-Label, Dose-Escalation, and Dose-Expansion Study of the Anti-CTLA-4 Monoclonal Antibody CS1002 As Monotherapy and in Combination with Anti-PD-1 Monoclonal Antibody CS1003 in Subjects with Advanced Solid Tumors

This is a multicenter, open-label, multiple dose, dose escalation phase I study to evaluate the clinical safety, tolerability, PK, and preliminary anti-tumor efficacy of CS1002.

Start Date26 Apr 2018

Sponsor / Collaborator

Cornerstone Pharmaceutical Co., Ltd

100 Clinical Results associated with Ipilimumab biosimilar (Cornerstone)

100 Translational Medicine associated with Ipilimumab biosimilar (Cornerstone)

100 Patents (Medical) associated with Ipilimumab biosimilar (Cornerstone)

Literatures (Medical) associated with Ipilimumab biosimilar (Cornerstone)

01 Jun 2024·Cancer

Dual CTLA‐4 and PD‐1 checkpoint blockade using CS1002 and CS1003 (nofazinlimab) in patients with advanced solid tumors: A first‐in‐human, dose‐escalation, and dose‐expansion study

Article

Author: Kotasek, Dusan ; Ma, Yiding ; Aghmesheh, Morteza ; Chan, Stephen L. ; Cosman, Rasha ; Zielinski, Robert ; Mant, Andrew ; Bishnoi, Sarwan ; Moore, Maggie ; Li, Peiqi ; Tse, Archie N. ; Pan, Zhaoxuan ; Yau, Thomas ; Prawira, Amy ; Su, Rila ; Eek, Richard ; Li, Fei

Abstract:

Background:

This study investigated the safety and efficacy of an anti–CTLA‐4 monoclonal antibody (CS1002) as monotherapy and in combination with an anti–PD‐1 monoclonal antibody (CS1003) in patients with advanced/metastatic solid tumors.

Methods:

The phase 1 study involved phase 1a monotherapy dose‐escalation (part 1) and phase 1b combination therapy dose escalation (part 2) and expansion (part 3). Various dosing schedules of CS1002 (0.3, 1, or 3 mg/kg every 3 weeks, or 3 mg/kg every 9 weeks) were evaluated with 200 mg CS1003 every 3 weeks in part 3.

Results:

Parts 1, 2, and 3 included a total of 13, 18, and 61 patients, respectively. No dose‐limiting toxicities or maximum tolerated doses were observed. Treatment‐related adverse events (TRAEs) were reported in 30.8%, 83.3%, and 75.0% of patients in parts 1, 2, and 3, respectively. Grade ≥3 TRAEs were experienced by 15.4%, 50.0%, and 18.3% of patients in each part. Of 61 patients evaluable for efficacy, 23 (37.7%) achieved objective responses in multiple tumor types. Higher objective response rates were observed with conventional and high‐dose CS1002 regimens (1 mg/kg every 3 weeks or 3 mg/kg every 9 weeks) compared to low‐dose CS1002 (0.3 mg/kg every 3 weeks) in microsatellite instability‐high/mismatch repair‐deficient tumors, melanoma, and hepatocellular carcinoma (50.0% vs. 58.8%, 14.3% vs. 42.9%, and 0% vs. 16.7%).

Conclusion:

CS1002, as monotherapy, and in combination with CS1003, had a manageable safety profile across a broad dosing range. Promising antitumor activities were observed in patients with immune oncology (IO)‐naive and IO‐refractory tumors across CS1002 dose levels when combined with CS1003, supporting further evaluation of this treatment combination for solid tumors.

Plain Language Summary:

CS1002 is a human immunoglobulin (Ig) G1 monoclonal antibody that blocks the interaction of CTLA‐4 with its ligands and increases T‐cell activation/proliferation. CS1003, now named nofazinlimab, is a humanized, recombinant IgG4 monoclonal antibody that blocks the interaction between human PD‐1 and its ligands.In this original article, we determined the safety profile of CS1002 as monotherapy and in combination with CS1003. Furthermore, we explored the antitumor activity of the combination in anti–programmed cell death protein (ligand)‐1 (PD‐[L]1)‐naive microsatellite instability‐high/mismatch repair‐deficient (MSI‐H/dMMR) pan tumors, and anti–PD‐(L)1‐refractory melanoma and hepatocellular carcinoma (HCC).CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising antitumor activities across CS1002 dose levels when combined with CS1003. This supports further assessment of CS1002 in combination with CS1003 for the treatment of solid tumors.

01 Jan 2017·BMJ openQ4 · MEDICINE

Rococo study: a real-world evaluation of an over-the-counter medicine in acute cough (a multicentre, randomised, controlled study)

Q4 · MEDICINE

ArticleOA

Author: Brew, J ; Wilson, R ; Edwards, V ; Kilbourn, A ; Morice, A H ; Birring, S S

Objectives:

To investigate the efficacy and safety of CS1002, an over-the-counter cough treatment containing diphenhydramine, ammonium chloride and levomenthol in a cocoa-based demulcent.

Design:

A multicentre, randomised, parallel group, controlled, single-blinded study in participants with acute upper respiratory tract infection-associated cough.

Setting:

4 general practitioner (GP) surgeries and 14 pharmacies in the UK.

Participants:

Participants aged ≥18 years who self-referred to a GP or pharmacist with acute cough of <7 days' duration. Participant inclusion criterion was cough severity ≥60 mm on a 0–100 mm visual analogue scale (VAS). Exclusion criteria included current smokers or history of smoking within the past 12 months (including e-cigarettes). 163 participants were randomised to the study (mean participant age 38 years, 57% females).

Interventions:

Participants were randomised to CS1002 (Unicough) or simple linctus (SL), a widely used cough treatment, and treatment duration was 7 days or until resolution of cough.

Main outcome measures:

The primary analysis was intention-to-treat (157 participants) and comprised cough severity assessed using a VAS after 3 days' treatment (prespecified primary end point at day 4). Cough frequency, sleep disruption, health status (Leicester Cough Questionnaire (LCQ-acute)) and cough resolution were also assessed.

Results:

At day 4 (primary end point), the adjusted mean difference (95% CI) in cough severity VAS between CS1002 and SL was −5.9 mm (−14.4 to 2.7), p=0.18. At the end of the study (day 7) the mean difference in cough severity VAS was −4.2 mm (−12.2 to 3.9), p=0.31. CS1002 was associated with a greater reduction in cough sleep disruption (mean difference −11.6 mm (−20.6 to 2.7), p=0.01) and cough frequency (mean difference −8.1 mm (−16.2 to 0.1), p=0.05) compared with SL. There was greater improvement in LCQ-acute quality of life scores with CS1002 compared with SL: mean difference (95% CI) 1.2 (0.05 to 2.36), p=0.04 after 5 days' treatment. More participants prematurely stopped treatment due to cough improvement in the CS1002 group (24.4%) compared with SL (10.7%; p=0.02). Adverse events (AEs) were comparable between CS1002 (20.5%) and SL (27.6%) and largely related to the study indication. 6 participants (7%) in the CS1002 group reduced the dose of medication due to drowsiness/tiredness, which subsequently resolved. These events were not reported by participants as AEs.

Conclusions:

Although the primary end point was not achieved, CS1002 was associated with greater reductions in cough frequency, sleep disruption and improved health status compared with SL.

Trial registration number:

EudraCT number2014-004255-31.

News (Medical) associated with Ipilimumab biosimilar (Cornerstone)

22 Nov 2021

·endpts.com

Two of China's top PD-(L)1 players team up on CTLA-4 in $200M deal

Now that the PD-(L)1 craze has (largely) swept through China, resulting in the approval of more than a dozen drugs with more to come, two of the top domestic oncology players are teaming up to go after the other checkpoint target. Hengrui is licensing exclusive China rights to CStone’s CTLA-4 inhibitor, CS1002, in a deal worth up to $200 million, which covers research, development, registration, manufacturing and commercialization. CStone is keeping the rest of world rights to itself — in this case meaning outside “Greater China.” Even though Chinese drug developers have been scouting global partners to co-develop and sell their homegrown drugs outside of China with fervor, tie-ups between local biopharma companies are still uncommon. The PD-(L)1 drugs from Hengrui and CStone have each earned the favor of US-based companies, with Incyte grabbing Hengrui’s camrelizumab as early as 2015 (before ultimately dropping it) and EQRx picking up CStone’s sugemalimab more recently. The new partners note that despite the early discovery of CTLA-4 — Jim Allison and Tasuku Honjo were awarded the Nobel Prize for it — and all the clinical validation of it as an I/O target, only one anti-CTLA-4 antibody has been approved globally (including in China). Without naming Yervoy, they added that the drug made $1.69 billion in 2020. “As a leading global China pharmaceutical company with an extensive oncology pipeline and strong integrated capabilities in commercialization, we are very confident that Hengrui will bring the full potentialities of CS1002 into the Greater China market,” CStone CEO Frank Jiang said in a statement. While CStone has a partnership with Blueprint Medicines to market two of its targeted cancer therapies in China, it does not have any commercial drug of its own. Citing results from an ongoing Phase Ia/Ib study, CStone touted how the combination of CS1002 and CS1003, a PD-1 blocker, was well-tolerated and demonstrated “very encouraging efficacy” in PD-(L)1-refractory melanoma and hepatocellular carcinoma, as well as PD-(L)1-naïve, pretreated microsatellite instability high/deficient mismatch repair (MSI-H/dMMR) tumors. While other CTLA-4 drugs have spurred concerns with toxicity or lack of efficacy, Lianshan Zhang, Hengrui’s president of R&D, expressed faith that CS1002’s “differentiated dosing schedules” will make it a backbone I/O asset.

AntibodyCollaborate

22 Nov 2021

·www.biospace.com

Two Chinese Biopharmas Align in $200 Million IO Deal

CStone Pharmaceuticals continues to expand its oncology presence aimed at the Chinese market. On Sunday, the company forged a licensing agreement with Jiangsu Hengrui Pharmaceuticals that grants the company access to a monoclonal antibody aimed at multiple forms of cancer. Currently, the only anti-CTLA-4 monoclonal antibody that has been approved globally is Bristol Myers Squibb's Yervoy, which was first approved by the U.S. Food and Drug Administration in 2011 and has also been approved for use in China. Yervoy generated approximately $1.69 billion in 2020. Based on its developmental data, CStone believes that CS1002 has the potential to carve away Yervoy’s revenue. CStone licensed CS1002, an investigational anti-CTLA-4 monoclonal antibody to Hengrui. Cytotoxic T lymphocyte associated antigen 4 (CTLA-4) is one of the few clinically validated targets for IO combination therapies. Based on previous preclinical and clinical studies, CStone believes that CS1002 has the potential to become a backbone therapeutic for multiple immuno-oncology combinations. And that evidence was strong enough for Hengrui to pay $200 million in upfront payment for the asset. Under terms of the deal, Hengrui gains the exclusive rights for research, development, manufacturing, and commercialization of CS1002 in Greater China. CStone will retain rights to market CS1002 outside of China. Lianshan Zhang, president of global R&D at Hengrui, said that the combination therapy potential of CS1002 will provide synergy with the company’s existing pipeline and bolster its competitiveness across China. “As a leading Chinese biopharmaceutical company, CStone has demonstrated its outstanding research and development capabilities with impressive early-stage clinical data and differentiated dosing schedules of CS1002. We have full confidence in the future development of it to provide more innovative drugs for Chinese patients,” Zhang said in a statement. Frank Jiang, chairman and chief executive officer of CStone, expressed his satisfaction of the agreement reached with Hengrui. “As a leading global China pharmaceutical company with an extensive oncology pipeline and strong integrated capabilities in commercialization, we are very confident that Hengrui will bring the full potentialities of CS1002 into the Greater China market. Through this collaboration, we believe we will join forces to bring forward more high-quality innovative oncology therapies to patients,” Jiang said in a statement. For CStone, the partnership with Hengrui follows a regulatory win in China for anti-PD-1 therapy. In September, China’s National Medical Products Administration approved the company’s checkpoint inhibitor sugemalimab as consolidation therapy in patients with unresectable stage III non-small-cell lung cancer. The company said the approval marks a first as sugemalimab becomes the “world’s first anti-PD-1/PD-L1 monoclonal antibody to significantly improve progression-free survival in patients with stage III non-small cell lung cancer (NSCLC) without disease progression after concurrent or sequential chemoradiotherapy.” In August, CStone saw the fruits of a partnership with Servier Pharmaceuticals after that company won U.S. approval for Tibsovo (ivosidenib tablets) for the treatment of adult patients with previously treated, locally advanced, or metastatic cholangiocarcinoma with an IDH1 mutation. Tibsovo is the first and only targeted therapy approved for patients with previously treated IDH1-mutated cholangiocarcinoma, a cancer of the bile ducts. CStone is no stranger to working with pharma giants. In 2019, the company partnered with Bayer, and then in 2020, CStone struck a partnership with Pfizer in support of the development of sugemalimab that included the pharma giant taking a $200 million stake in the company.

CollaborateAntibodyInnovative Drug

100 Deals associated with Ipilimumab biosimilar (Cornerstone)

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 1	CN	Jiangsu Hengrui Pharmaceuticals Co., Ltd.	21 Nov 2021
Advanced Malignant Solid Neoplasm	Phase 1	AU	Cornerstone Pharmaceutical Co., Ltd	26 Apr 2018
Advanced Malignant Solid Neoplasm	Phase 1	HK	Cornerstone Pharmaceutical Co., Ltd	26 Apr 2018

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03523819 (ESMO_IO2021) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	36	CS1002+CS1003 (MSI-H/dMMR tumors or MEL + arm A)	cgwnjqlbby(ubmxpeorpt) = 5 (9.3%) pts had AEs leading to discontinuation of CS1002 and CS1003. dzswapsueq (kalfkdafvz ) View more	Positive	09 Dec 2021
				CS1002+CS1003 (MSI-H/dMMR tumors or MEL + arm B)
NCT03523819 (ESMO2021) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	33	CS1003 200 mg+CS1002 0.3 mg/kg	fcknpmewoo(lbqdxvnxwt) = Two (6.1%) pts experienced AEs leading to discontinuation of CS1002 and CS1003. yaidocppwd (zobpjjfiik )	Positive	16 Sep 2021
				CS1003 200 mg+CS1002 1 mg/kg

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