Phase I/II Clinical Study of CVL006 Combination Therapy in Advanced Solid Tumors
Overview
- Phase
- Phase 1
- Status
- Not yet recruiting
- Enrollment
- 318
- Locations
- 1
- Primary Endpoint
- DLT and RP2D of phase I
Overview
Brief Summary
This study is a multi-center, open-label, dose-escalation and dose-optimized phase I/II clinical trial. Objective: To determine the safety, tolerability, PK characteristics and preliminary efficacy data of CVL006 combined with pemetrexed + carboplatin/SKB264/ DS-8201a/ Enfortumab Vedotin in patients with advanced solid tumors.
Detailed Description
- Phase I Arm1.1 - Arm1.4: Dose escalation of CVL006 combined with pemetrexed + carboplatin/SKB264/ DS-8201a/ Enfortumab Vedotin: Dose escalation studies of CVL006 combined with pemetrexed + carboplatin/SKB264/DS-8201a/ Enfortumab Vedotin can be conducted simultaneously, with two dose groups preset for each combination: The starting Dose (Dose Level1 [DL1]) of CVL006 is 3mg/kg or more (the investigator and the sponsor can discuss and decide on a dose of 3mg or more based on more data from the Phase I monotherapy study), Q2W or Q3W administration, and DL2 (one dose group higher than DL1) dose. Arm1.1 to Arm1.4 Each cohort is expected to increase to 6 to 12 subjects. Based on the data such as safety, tolerability, efficacy and PK characteristics observed during the dose escalation process of each cohort, the researcher and the sponsor jointly decided whether to adopt the Backfill design, that is, to enroll additional patients in the confirmed safe low-dose group during the dose escalation process. And decide whether to explore other administration doses or frequencies (such as Q3W).
- Phase II Dose optimization study In order to further evaluate the PK characteristics, safety and preliminary anti-tumor activity of CVL006 combined with pemetrexed + carboplatin/SKB264/ DS-8201a/ Enfortumab Vedotin, while the dose escalation trial of phase I was being conducted, Several dose groups that have passed the safety assessment during the DLT observation period will be selected to conduct the Phase II dose expansion study simultaneously. If, based on the obtained safety, tolerability, PK and efficacy information, the investigator and the sponsor discuss and decide on the choice of dose expansion and the specific number of cases to be increased. And whether a new dose needs to be added for dose expansion. Similarly, for each cohort with a new dose or a new administration frequency, the number of subjects in each group should be increased to 8-30 (subjects who previously used the same dose can be included).
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age: 18 to 75 years old (including both ends), gender not limited;
- •Stage I Arm1.1, Arm1.2, Arm1.3 and Arm1.4: Locally advanced, recurrent or metastatic solid tumors confirmed by histology or cytology, with previous treatment failure.
- •Phase II Arm2.1, Arm2.2, Arm2.5 and Arm2.7: For NSCLC Arm2.1: Non-squamous, wild-type NSCLC Arm2.2: EGFRm nsqNSCLC Arm2.3: Malignant pleural mesothelioma Arm2.4: triple-negative breast cancer Arm2.5: EGFRm nsqNSCLC Arm2.6: breast cancer Arm2.7: NSCLC Arm2.8: adenocarcinoma of the stomach or gastroesophageal junction Arm2.9: urothelial carcinoma
- •All subjects must provide tumor tissue samples for PD-L1 testing: Tumor tissue samples should preferably be newly obtained tumor tissues. For subjects who cannot provide newly obtained tissues, tumor tissue samples archived within 3 years prior to the first study treatment can be provided. The sample type should be neutral formalin-fixed and paraffin-embedded \[FFPE\] tissue wax blocks or at least 6 unstained tumor tissue sections. If the number is less than 6 pieces, it is necessary to negotiate with the sponsor and only allow enrollment after obtaining consent.
- •ECOG overall performance status (PS) 0-1 point;
- •Predicted survival period ≥ 3 months;
- •According to the efficacy evaluation criteria for solid tumors (RECISTv 1.1), there is at least one measurable lesion;
- •Have sufficient bone marrow and organ function (no blood components and/or cell growth factors have been used within 14 days prior to the start of the study treatment) :
- •Hemoglobin (HB) ≥ 90 g/L;
- •Neutrophil count (ANC) ≥1.5×109/L;
Exclusion Criteria
- •Accompanied by untreated or active central nervous system (CNS) tumor metastasis. Subjects with a history of meningeal metastasis or those currently having meningeal metastasis.
- •Patients with other malignant tumors, excluding fully treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, local prostate cancer after radical resection, ductal carcinoma in situ after radical resection, papillary thyroid carcinoma after radical resection, or those with other malignant tumors, must have at least a 3-year tumor-free period.
- •For those whose tumor lesions are judged by researchers to have a bleeding tendency, such as those whose imaging examinations during the screening period show that the subjects have: imaging evidence of tumor invasion or encirclement of large blood vessels;
- •Exclude subjects who have previously used VEGF/PD-1 (PD-L1) bispecific antibodies; Subjects who have previously received targeted therapy with TROP2, HER2 or Nectin-4, ADC, or any study drugs containing MMAE and whose treatment duration is less than 6 months should also be excluded. Subjects who had previously used bevacizumab were excluded.
- •Previously used immune checkpoint agonist therapy (such as CD137 agonists), anti-CD73 inhibitors, immune checkpoint inhibitors (such as anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, etc.), and immune cell therapy (such as CAR-T) And other treatments targeting the tumor immune mechanism are not allowed to be enrolled.
- •It is known that there is an allergic reaction to CVL006, SKB264, T-DXd, Enfortumab Vedotin, pemetrexel or platinum-based or any excipient component of the study drug (including histidine, trehalose and polysorbide 20), or there is a history of severe allergic reaction to other monoclonal antibodies;
- •Have serious cardiovascular and cerebrovascular diseases, including but not limited to:
- •Severe cardiac rhythm or conduction abnormalities within 6 months prior to the first use of the study drug, such as ventricular arrhythmias requiring clinical intervention, II-III degree atrioventricular block, etc.
- •Acute coronary syndrome, congestive heart failure (New York Heart Association (NYHA) cardiac function classification ≥ grade II), and aortic dissection occurred within 6 months prior to the first use of the study drug;
- •There have been arteriovenous thrombotic events such as cerebrovascular accidents (transient ischemic attack, cerebral hemorrhage, stroke), deep vein thrombosis and pulmonary embolism, etc. within 6 months before the first use of the study drug;
Arms & Interventions
Arm 1.1
Patients with advanced solid tumors were enrolled in Arm1.1. The medication used was CVL006 combined with pemetrexed and carboplatin. Two dose groups were preset. The starting dose of CVL006 for DL1 was 10mg/kg (administered at Q2W or Q3W), and for DL2 (one dose higher than DL1). Pemetrexed + carboplatin was a fixed dose. Each dose group enrolled 3 to 6 patients, and Arm1.1 enrolled a total of 6 to 12 patients.
Intervention: CVL006 combined with pemetrexed and carboplatin (Drug)
Arm 1.2
Patients with advanced solid tumors were enrolled in Arm1.2, and the medication used was CVL006 combined with SKB264. Two dose groups were preset. The starting dose of CVL006 for DL1 was 10mg/kg (administered at Q2W or Q3W), and for DL2 (one dose group higher than DL1). SKB264 was a fixed dose. Each dose group enrolled 3 to 6 patients, and Arm1.2 enrolled a total of 6 to 12 patients.
Intervention: CVL006 in combination with SKB264 (Drug)
Arm 1.3
Patients with advanced solid tumors were enrolled in Arm1.3, and the medication used was CVL006 combined with DS-8201a. Two dose groups were preset. The starting dose of CVL006 for DL1 was 10mg/kg (administered at Q2W or Q3W), and the dose for DL2 (one dose group higher than DL1). DS-8201a was a fixed dose. Each dose group enrolled 3 to 6 patients respectively, and Arm1.3 enrolled a total of 6 to 12 patients.
Intervention: CVL006 in combination with DS-8201 (Drug)
Arm1.4
Patients with advanced solid tumors were enrolled in Arm1.4 and treated with CVL006 combined with Enfortumab Vedotin. Two dose groups were preset. The starting dose of CVL006 for DL1 was 10mg/kg (administered at Q2W or Q3W), and the dose of DL2 (one dose group higher than DL1). Enfortumab Vedotin was a fixed dose. 3 to 6 patients were enrolled in each dose group, and 6 to 12 patients were enrolled in Arm1.4.
Intervention: CVL006 in combination with Enfortumab Vedotin (Drug)
Arm2.1
NSCLC patients were enrolled in Arm2.1. The medication used was CVL006 combined with pemetrexed and carboplatin. 8 to 30 patients were enrolled.
Intervention: CVL006 combined with pemetrexed and carboplatin (Drug)
Arm2.2
Patients with EGFRm nsqNSCLC were enrolled in Arm2.2. The medication used was CVL006 combined with pemetrexed and carboplatin. 8 to 30 patients were enrolled.
Intervention: CVL006 combined with pemetrexed and carboplatin (Drug)
Arm2.3
Patients with malignant pleural mesothelioma were enrolled in Arm2.3. The medication used was CVL006 combined with pemetrexed and carboplatin. 8 to 30 patients were enrolled.
Intervention: CVL006 combined with pemetrexed and carboplatin (Drug)
Arm2.4
Breast cancer patients were enrolled in Arm2.4, and the medication used was CVL006 combined with SKB264. 8 to 30 patients were enrolled.
Intervention: CVL006 in combination with SKB264 (Drug)
Arm2.5
Patients with EGFRm nsqNSCLC were enrolled under Arm2.5, with the medication being CVL006 combined with SKB264. 8 to 30 patients were enrolled.
Intervention: CVL006 in combination with SKB264 (Drug)
Arm2.6
Breast cancer patients were enrolled in Arm2.6, and the medication used was CVL006 combined with DS-8201a. 8 to 30 patients were enrolled.
Intervention: CVL006 in combination with DS-8201 (Drug)
Arm2.7
NSCLC patients were enrolled in Arm2.7. The medication used was CVL006 combined with DS-8201a. 8 to 30 patients were enrolled.
Intervention: CVL006 in combination with DS-8201 (Drug)
Arm2.8
Patients with adenocarcinoma of the stomach or gastroesophageal junction were enrolled under Arm2.8. The medication used was CVL006 combined with DS-8201a. 8 to 30 patients were enrolled.
Intervention: CVL006 in combination with DS-8201 (Drug)
Arm2.9
Patients with urothelial carcinoma were enrolled under Arm2.9. The medication used was CVL006 combined with Enfortumab Vedotin. 8t to 30 patients were enrolled.
Intervention: CVL006 in combination with Enfortumab Vedotin (Drug)
Outcomes
Primary Outcomes
DLT and RP2D of phase I
Time Frame: 28 days after the first medication; If the second administration is delayed, the DLT observation period will be extended to 14 days after the second administration
DLT and RP2D of phase I (Arm1.1, Arm1.2, Arm1.3 and Arm1.4) CVL006 combined with pemetrexed + carboplatin/SKB264/ DS-8201a/ Enfortumab Vedotin in patients with advanced solid tumors
Phase II, progression-free survival (PFS) according to RECISTv1.1 criteria
Time Frame: Imaging examinations should be conducted every 8 weeks (±7 days) after the initiation of administration
The efficacy of phase II CVL006 combined with pemetrexed + carboplatin /SKB264/ DS-8201a/ Enfortumab Vedotin in the treatment of advanced solid tumors: progression-free survival (PFS) according to RECISTv1.1 criteria
Safety endpoints for phase I and Phase II
Time Frame: From date of randomization until the date of first documented progression, assessed up to 36 months
Number of participants with adverse events (AE)/serious adverse events (SAE)
Secondary Outcomes
- Pharmacokinetic (PK) parameters of CVL006 in Phase I and Phase II(From date of randomization until the date of first documented progression, assessed up to 36 months)
- Efficacy endpoints for Phase I and Phase II(From date of randomization until the date of first documented progression, assessed up to 36 months)
- ADA&Nab(From date of randomization until the date of first documented progression, assessed up to 36 months)
- PD-L1 expression(From date of randomization until the date of first documented progression, assessed up to 36 months)