Prospective registration

A phase Ib/II, multi-center, open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of subcutaneous administration of DN1508052-01 combined with Toripalimab to adult patients with advanced solid tumors that progressed, intolerant to standard therapy or for which no standard therapy

A study to evaluate the preliminary antitumor activity of subcutaneous administration of DN1508052-01 combined with Toripalimab to adult patients with advanced solid tumors

A phase Ib/II, multi-center, open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of subcutaneous administration of DN1508052-01 combined with Toripalimab to adult patients with advanced solid tumors that progressed, intolerant to standard therapy or for which no standard therapy

Xiaonan Guo 

Lin Shen 

2-3 Floors, West Side, Building 1, 230 Cailun Road, 86 Faraday Road, Pilot Free Trade Zone, Shanghai, China

52 Fucheng Road, Haldlan District, Beijing, China

Shanghai De Novo Pharmatech Co., Ltd.

Beijing Cancer Hospital

Yes

Ethics Committee of Beijing Cancer Hospital

Jie Li

81 Fucheng Road, Haidian District, Beijing, China

Beijing Cancer Hospital

81 Fucheng Road, Haidian District, Beijing, China

Shanghai De Novo Pharmatech Co., Ltd.

solid tumor

Interventional study

1-2

Cohort study 

Part 1 (Dose-Escalation) Primary objectives: To determine the maximum tolerated dose (MTD) and recommended phase Ⅱ dose (RP2D) for subcutaneous administration of DN1508052-01 (DN052) combined with toripalimab (JS001) in adult patients with advanced solid tumors. Secondary objectives: 1. To characterize the safety and tolerability of DN052 combined with JS001 in patients with advanced solid tumors; 2. To evaluate the preliminary antitumor activity of DN052 combined with JS001; 3. To determine the pharmacokinetic (PK) profiles of DN052 combined with JS001; 4. To determine the pharmacodynamics (PD) profiles of DN052 combined with JS001; 5. To explore the relationship between biomarkers (PD-L1) and/or Epstein-Barr Virus (EBV) and/or human papilloma virus (HPV) positive and antitumor activity of DN052 combined with JS001. Part 2 (Dose-Expansion) Primary objectives: To evaluate the preliminary antitumor activity of DN052 combined with JS001. Secondary objectives: 1. To evaluate the preliminary efficacy of DN052 combined with JS001 by other efficacy endpoints; 2. To evaluate the safety and tolerability of DN052 combined with JS001; 3. To determine the pharmacokinetic (PK) profiles of DN052 combined with JS001; 4. To determine the pharmacodynamics (PD) profiles of DN052 combined with JS001; 5. To explore the relationship between biomarkers (PD-L1) and/or Epstein-Barr Virus (EBV) and/or human papilloma virus (HPV) positive and antitumor activity of DN052 combined with JS001.

1.Investigational Products (1) DN1508052-01 (DN052) Dosage form: lyophilized powder; Specification: 5 mg/vial (2) Toripalimab (JS001) Dosage form: injection; Specification: 240 mg (6 mL) /bottle 2. Administration and preparation (1) DN052 Add 1 mL of sterile water into DN052 at room temperature (invert the vial and shake gently for about 1 minute until the drug is completely dissolved), then use 0.9% sodium chloride for dilution according to the calculated dose for single-site injection (the volume of each single-site injection <= 1 mL). The injection should be performed within 6 hours. As the dose increases, multiple-site injections may be required. After each injection, the remaining DN052 will be discarded and cannot be reused. (2) JS001 Slowly inject the prespecified volume of JS001 into the infusion bag containing 100 mL normal saline (0.9% sodium chloride) to prepare a dilution with a final concentration of 1-3 mg/mL. Gently invert and mix it for intravenous infusion. The tube used for infusion must be equipped with a sterile, pyrogen-free, low protein binding infusion tube filter (pore size 0.2 or 0.22 μm). The preparation of the diluent should be completed within 24 hours after the product is taken out of the refrigerator. The diluent prepared under aseptic operation should be placed at room temperature or at 2-8°C for no more than 8 hours. This includes the time of storing in the infusion bag at room temperature and the duration of the infusion process. It is recommended to use it within 4 hours. The product cannot be frozen and must be used after returning to room temperature if refrigerated. The detail information of the administration and preparation of DN052 and JS001 can be found in the Investigational Product Management Plan. 3. Regimen (1) Subcutaneous administration of DN052 The deltoid muscle of the upper arm was chosen as the subcutaneous injection site. Alternate injections were performed in the deltoid muscles of the upper arms bilaterally. The injection site can alternate between the lower and upper borders of the deltoid muscle with each injection. The selection of each injection point should be no less than 1cm away from the previous injection point. If both upper arms cannot be injected due to injection site reactions (ISRs) or other reasons, the abdominal wall and the anterolateral thigh can be selected as alternative injection sites. DN052 will be administered subcutaneously on Day 1 (Day -1 if patient underwent PK sampling at the first cycle), Day 8 and Day 15 of each 21-day cycle. The prespecified regimen of DN052 may be adjusted based on the opinion of investigator and sponsor in terms of the safety profile, PK/PD and other results during the study period. In addition, patients should orally administer 650 mg acetaminophen within 30 minutes before each administration of DN052. Due to the risk of Cytokine Release Syndrome (CRS), patients should be monitored for a minimum of 12 hours following administration of the first two doses of DN052. The subsequent administration of DN052 following the below criteria: 1) If there is no evidence of CRS after the first two doses, then the duration of monitoring can be decreased to a minimum of 2 hours after each dose. 2) If patients who have signs or symptoms of CRS in a prior cycle, the patients would be observed for a minimum of 12 hours following each administration of DN0052 (if remaining on treatment). 3) If patients require corticosteroids or antihistamines for signs/symptoms of hypersensitivity, then they should be observed for a minimum of 24 hours. (2) Intravenous administration of JS001 Intravenous infusion of JS001 (240 mg) will be conducted 30 min (±10 min) after the first administration of DN052 at each cycle of the treatment. The first intravenous infusion of JS001 should take at least 60 min. If the first infusion is well-tolerated, the duration of the second infusion can be shortened to at least 30 min. If the second infusion is also well-tolerated by the patient, all subsequent infusions can be shortened to at least 30 minutes as well. The administration of JS001 should not be administered as an intravenous bolus or a single bolus intravenous injection. 

1. Patients who have a history of another primary malignancy within 2 years before screening, with the exception of cured cutaneous squamous cell carcinoma, skin basal cell carcinoma, non-muscle-invasive bladder cancer, localized low-risk prostate cancer [stage <= T2a, Gleason score <= 6, and PSA <= 10 ng/mL (if measured) at diagnosis of prostate cancer who had received curative treatment and had no prostate-specific antigen (PSA) biochemical recurrence are eligible to participate in the study], and carcinoma in situ of cervix/breast;
2. Patients with brain metastases, spinal cord compression, or carcinomatous meningitis; otherwise, has remained neurologically stable < 4 weeks (no new neurologic deficits from brain metastasis on Screening clinical examination, no new findings on CNS imaging, and no corticosteroids being used);
3. Patients who have any severe and/or uncontrolled medical conditions or other conditions such as:
(1) Patients with a history of active tuberculosis;
(2) Patients who have a known diagnosis of congenital or acquired immunodeficiency, such as HIV-infected patients or those with a history of AIDS;
(3) Patients with HBV and HCV infection;
(4) HBsAg positive patients need to be tested for HBV DNA. Active hepatitis B patients with HBV DNA quantification < 500 IU/mL and has received antiviral therapy (interferon therapy is not allowed) for 14 days prior to treatment who are willing to continue antiviral therapy during the study period can be enrolled; Patients with positive HCV RNA (HCV RNA quantification > 103 copies/mL) who are willing to continue antiviral therapy according to local standard treatment and whose liver function meets the inclusion criteria can be enrolled; Patients with a history of HCV infection but has negative PCR results for HCV RNA can be enrolled;
(5) Patients received systemic corticosteroids (intravenous or broad-spectrum oral antibiotics for more than 1 week) within 28 days prior to the first administration of investigational product;
4. Patients with active or previous autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc.), except for patients with clinically stable autoimmune thyroid disease;
5. Patients who with an allo-transplant of any kind (including those with a xenograft heart valve);
6. Any significant ophthalmologic abnormality, including but not limited to the following:
(1) Grade 2 or greater severity syndrome of dry eye;
(2) Iritis.
7. Patients who have a history of definite neurological disorders that affected brain function activity, including epilepsy or dementia;
8. Patients with thrombotic or embolic events, such as cerebrovascular accident, uncontrolled deep vein thrombosis, pulmonary embolism, etc., within 6 months prior to the first dose of investigational product; Patients who is currently receiving thrombolytic or anticoagulant therapy such as warfarin, heparin, or similar drugs, or long-term nonsteroidal anti-inflammatory drug (NSAID) therapy; Prophylactic anticoagulation by open intravenous delivery systems is permitted, as long as the coagulation conditions required for enrollment are met within 7 days prior to initiation of investigational product;
9. Patients with clinically significant bleeding, or a clear bleeding tendency, such as gastroesophageal varices, gastrointestinal bleeding, hemorrhagic gastric ulcer, etc. within 3 months before the start of administration; patient with clinically significant hemoptysis within 2 months before the start of administration; patients with potential visceral hemorrhage in the investigator's opinion;
10. Patients with past or current interstitial lung disease (patients with radiation pneumonitis who do not require hormone therapy can be enrolled), or patients with a history of non-infectious pneumonitis;
11. Patients who have impaired cardiac function or clinically significant cardiac diseases, including any of the following:
(1) Patients with severe cardiac arrhythmias or conduction abnormalities, such as ventricular arrhythmia and grade II-III atrioventricular block that requiring clinical intervention;
(2) Baseline QT interval corrected for heart rate using Fridericias formula >4 80 msec or congenital long QT syndrome;
(3) Any of the following within 6 months prior to the first dose of investigational product: acute coronary syndrome, congestive heart failure, aortic dissection, stroke, and other grade 3 or higher cardiovascular and cerebrovascular events;
(4) NYHA Class II or higher congestive heart failure;
(5) Left ventricular ejection fraction (LVEF) < 50% assessed by echocardiogram;
(6) Uncontrolled hypertension (systolic blood pressure >= 160 mmHg or diastolic blood pressure >= 100 mmHg.
12. Patients received local therapy (including but not limited to TACE, radiotherapy, radiofrequency ablation, microwave ablation), systemic targeted therapy, immunotherapy, chemotherapy, and non-palliative radiotherapy (palliative radiotherapy for bone pain relief is permitted, but must be completed at least 2 weeks prior to dosing) within 4 weeks prior to the start of administration; patients received immune modulators or inhibitors, such as IL-2, interferon and thymosin, anti-TNF-α drugs, etc. within 2 weeks before administration; patients received National Medical Products Administration (NMPA)-approved traditional Chinese anti-tumor medication within 2 weeks before administration; patients received live vaccines (including live-attenuated vaccines) within 4 weeks before dosing and/or who plan to receive live vaccines after enrollment; patients received medications from other clinical trial within 4 weeks before administration;
13. AEs from previous anti-tumor therapy have not recovered to grade 1 or below based on CTCAE 5.0 (excluding cases of (1) Aalopecia; (2) Pigmentation; (3) Grade 2 long-term toxicity caused by radiotherapy that in the opinion of the investigators, cannot be recovered; (4) Grade 2 neurotoxicity caused by platinum; (5) Hemoglobin >= 90 g/L and < 100 g/L with no safety risk in the opinion of the investigators);
14. Patients received PD-1/PD-L1 immune checkpoint inhibitors and presented with Grade >= 3 immune-related adverse events (IRAE, except from Grade 3 immune-related endocrine adverse events and Grade 3 immune-related cutaneous toxicity that can be controlled by replacement therapy), Grade >= 2 immune-related pneumonia, >= Grade 2 immune-related central nervous system toxicity, or >= Grade 1 immune-related myocarditis; patients with rapid progression after administration of PD-1/PD-L1 immune checkpoint inhibitors; patients received PD-1/PD-L1 immune checkpoint inhibitors within 2 months before dosing;
Rapid progression is defined as meeting at least one of the following criteria: (1) Time to treatment failure (TTF, from the first administration of PD-1/PD-L1 treatment to the end of treatment for any reason, including disease progression, toxicity or death, etc.) ≤2 months; (2) The diameters of target lesion increases >= 50% from baseline at first imaging assessment; (3) The tumor growth rate (TGR) after immunotherapy was 2 times higher compared to the previous rate;
15. Patients received potent CYP3A4 inducer or inhibitor within 2 weeks prior to administration of the first dose of study drug on Day 1;
16. Patients received systemic corticosteroids (Prednisone > 10 mg/day or other competitors with the equivalent dose) or other immunosuppressive treatments within 2 weeks prior to administration of the first dose of study drug on Day 1. Except from treatment with topical, ocular, intra-articular, intranasal, and inhaled glucocorticoids; short-term glucocorticoid prophylaxis (e.g., prophylaxis of contrast media allergy);
17. Patients who have a history of Grade 3 or higher allergic reactions (significant urticaria, angioedema, anaphylaxis);
18. Treated with TLR8 immunomodulators (e.g., motolimod, GS9688, IMO4200, E-6742, E-6887, etc.);
19. Patients who had or scheduled major surgery (does not include needle biopsy) for any cause within 4 weeks of first dosing;
20. Pregnancy or lactation;
21. Patients with any comorbid medical disorder that, in the opinion of the investigator or sponsor, may increase the risk of toxicity.

open label

None

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