A Phase I/II Dose-Escalation and Efficacy/Safety Study of Afuresertib Plus Sintilimab Plus Chemotherapy in Patients With Selected Solid Tumors That Resistance to Prior Anti-PD-1/PD-L1 Treatment
Overview
- Phase
- Phase 1
- Intervention
- Afuresertib
- Conditions
- Solid Tumor
- Sponsor
- Laekna Limited
- Enrollment
- 167
- Locations
- 5
- Primary Endpoint
- Phase I: Frequency and severity of Adverse Events (AEs),including incidence rate of DLTs
- Status
- Completed
- Last Updated
- 5 months ago
Overview
Brief Summary
This is a multicenter, open-label, dose-escalation and efficacy/safety Phase I/II study to assess RP2D, safety, tolerability and anti-tumor activity of Sintilimab + afuresertib + nab-paclitaxel or docetaxel administered as a combination therapy.
This study is designed to identify the MTD and recommended Phase II dose (RP2D) of afuresertib in combination with sintilimab and nab-paclitaxel or docetaxel, respectively, to characterize the PK profile of afuresertib in phase I and to evaluate clinical efficacy and safety of the combination therapy in phase II. The study population in phase II is the patients with one of the five selected cancers who resistant to the prior anti-PD-1/PL-1 treatments (as a monotherapy or in combination with other anti-cancer drugs including chemotherapy) , such as EC, GC/GEJC, EsC, CC, and NSCLC.
Detailed Description
This is a multicenter, open-label, dose-escalation and efficacy/safety Phase I/II study to assess RP2D, safety, tolerability and anti-tumor activity of Sintilimab + afuresertib + nab-paclitaxel or docetaxel administered as a combination therapy. This study is designed to identify the MTD and recommended Phase II dose (RP2D) of afuresertib in combination with sintilimab and nab-paclitaxel or docetaxel, respectively, to characterize the PK profile of afuresertib in phase I and to evaluate clinical efficacy and safety of the combination therapy in phase II. The study population in phase II is the patients with one of the five selected cancers who resistant to the prior anti-PD-1/PL-1 treatments (as a monotherapy or in combination with other anti-cancer drugs including chemotherapy) , such as EC, GC/GEJC, EsC, CC, and NSCLC. For phase I, the MTD is defined as the combination dose level with a DLT rate that is closest to the target toxicity rate (0.3). Patients in each dose level are planned to be enrolled in each cohort of size 3 and maximum to 9. Totally there would be no more than 42 cases in 2 combination groups (maximum 21 patients for each combination group). RP2D evaluation will be based on the observed safety profiles,PK ，PK was analyzed on 3-9 patients per dose of albumin-paclitaxel and docetaxel (pk Sample collection may be less than 3 if the group was discontinued due to DLT observed) . The dose escalation decision will be made based on the observed safety profiles of the tested combined doses and reviewed by the safety committee. The recommended combined dose level will be as follows based on BOIN dose escalation design. Once the RP2D of Sintilimab + afuresertib + nab-paclitaxel or docetaxel has been established, a cohort consisting of 50-125 patients with stratifying for each cancer type (10 -25 patients for each cancer type) who resistant to anti-PD-1/PD-L1 or its combination therapy (except for CC and EC, who did not receive prior anti-PD-1/PD-L1 could be enrolled. The preliminary anti-tumor efficacy of Sintilimab + afuresertib + nab-paclitaxel or docetaxel therapy will be assessed by the measurement of ORR, PFS, OS, DOR, DCR based on the tumor assessment in each of the five solid tumors. Patients with biomarkers, such as PTEN/PI3K/AKT alternations, will be analysed retrospectively as the subpopulations for their anti-tumor efficacy in each cancer type.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Be \>=18 years of age on the day of signing the informed consent and be able to provide written informed consent for the trial.
- •Prior treatments:
- •In phase I, patients had at least 1 prior systemic anti-cancer treatment (including neoadjuvant/adjuvant therapy are qualified to be enrolled). Patients who resistant to anti-PD-1/PD-L1 are preferred.
- •In phase II, patients should meet the following 2 criteria simultaneously:
- •A: resistant to anti-PD-1/PD-L1: previously received at least 6 weeks （2 cycles） anti-PD-1/PD-L1 (including neoadjuvant/adjuvant therapy) and progressed after anti-PD-1/PD-L1 or their combination therapies.
- •B: received \<=3 lines systematic therapy during recurrent/metastatic period.
- •Tumor diagnosis:
- •In phase I, patients had a histology confirmed diagnosis of locally advanced or metastatic solid tumors who had at least 1 prior systemic anti-cancer treatment including neoadjuvant/adjuvant therapy are qualified to be enrolled. The patients with the 5 selected cancer types below who resistant to prior anti-PD-1/PL-1 or its combination therapies will be enrolled with a higher priority.
- •In phase II, the patients have only the following diagnoses will be allowed:
- •CC: Patients with histologically confirmed metastatic, recurrent or persistent squamous cell carcinoma, adenosquamous carcinoma, adenocarcinoma of the cervix are allowed. The other histological types of cervical cancer will be excluded.
Exclusion Criteria
- •Pregnancy or lactation. A woman of child-bearing potential, who has a positive urine pregnancy test prior to treatment. If the urine test is cannot be confirmed as negative, a serum pregnancy test will be required.
- •Prior anti-cancer treatment or any investigational agent within 28 days (or 5 half-lives, whichever is shorter) prior to the first dose of study drugs.
- •Patients that have previously received AKT or PI3 kinase pathway or mTOR inhibitors will not be enrolled.
- •Patients that discontinued prior anti PD-1/PD-L1 due to immune related AE.
- •Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
- •With clinically uncontrolled pleural effusion/ascites (patients who do not need effusion drainage or have no significant increase in effusion 3 days after stopping drainage can be enrolled);
- •With a tumor compressing the surrounding important organs, compressing the superior vena cava, or invading the mediastinal great vessels, heart, etc.;
- •Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
- •Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, transitional cell carcinoma of urothelial cancer, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
Arms & Interventions
Afuresertib in combination with Sintilimab and Nab-paclitaxel
Afuresertib in combination with Sintilimab and Nab-paclitaxel in patients with Endometrial Cancer and Cervical Cancer
Intervention: Afuresertib
Afuresertib in combination with Sintilimab and Nab-paclitaxel
Afuresertib in combination with Sintilimab and Nab-paclitaxel in patients with Endometrial Cancer and Cervical Cancer
Intervention: Nab paclitaxel
Afuresertib in combination with Sintilimab and Nab-paclitaxel
Afuresertib in combination with Sintilimab and Nab-paclitaxel in patients with Endometrial Cancer and Cervical Cancer
Intervention: Sintilimab
Afuresertib in combination with Sintilimab and Docetaxel
Afuresertib in combination with Sintilimab and Docetaxel in patients with Gastric and Gastroesophageal Junction Adenocarcinoma, Non-Small Cell Lung Cancer and Esophageal Cancer
Intervention: Afuresertib
Afuresertib in combination with Sintilimab and Docetaxel
Afuresertib in combination with Sintilimab and Docetaxel in patients with Gastric and Gastroesophageal Junction Adenocarcinoma, Non-Small Cell Lung Cancer and Esophageal Cancer
Intervention: Docetaxel
Afuresertib in combination with Sintilimab and Docetaxel
Afuresertib in combination with Sintilimab and Docetaxel in patients with Gastric and Gastroesophageal Junction Adenocarcinoma, Non-Small Cell Lung Cancer and Esophageal Cancer
Intervention: Sintilimab
Outcomes
Primary Outcomes
Phase I: Frequency and severity of Adverse Events (AEs),including incidence rate of DLTs
Time Frame: Through study completion for an average of 12 months
Phase I: Findings on physical examination, ECG, vital signs, and reports of the laboratory results based on the CTCAE v5.0
Phase I: Recommended Phase II dose
Time Frame: about 12 months
Phase I: Determining the RP2D of the Combination therapy for phase II
Phase II: Overall Response Rate (ORR) based on RECIST 1.1
Time Frame: Change from Baseline beginning at Cycle 3 Day 1 and then every 6 weeks × 18weeks then every 9 weeks through study completion, an average of 2 years (each cycle is 21 days)
Anti-tumor activity of Afuresertib in combination with Sintilimab and Nab-paclitaxel or Docetaxel in EC/CC/ GC/GEJC/EsC/NSCLC
Secondary Outcomes
- Assessing pharmacokinetics parameters(Assessed on Day 1, Day 15 of Cycle 1 and Day1 of Cycle 3 (each cycle is 21 days))
- Phase I：Overall Response Rate (ORR) based on RECIST 1.1(Change from Baseline beginning at Cycle 3 Day 1 and then every 6 weeks × 18weeks then every 9 weeks through study completion, an average of 1 year (each cycle is 21 days))
- Progression Free Survival (PFS) based on RECIST 1.1(Change from Baseline beginning at Cycle 3 Day 1 and then every 6 weeks × 18weeks then every 9 weeks through study completion, an average of 1 year (each cycle is 21 days))
- Disease Control Rate (DCR) based on RECIST 1.1(Change from Baseline beginning at Cycle 3 Day 1 and then every 6 weeks × 18weeks then every 9 weeks through study completion, an average of 1 year (each cycle is 21 days))
- Phase II: Overall Response Rate (ORR) based on immune-related iRECIST(Change from Baseline beginning at Cycle 3 Day 1 and then every 6 weeks × 18weeks then every 9 weeks through study completion, an average of 2 years (each cycle is 21 days))
- Phase II: Overall Survival (OS) based on RECIST 1.1(Change from Baseline beginning at Cycle 3 Day 1 and then every 6 weeks × 18weeks then every 9 weeks through study completion, an average of 2 years (each cycle is 21 days))
- Duration of Response (DOR) based on RECIST 1.1(Change from Baseline beginning at Cycle 3 Day 1 and then every 6 weeks × 18weeks then every 9 weeks through study completion, an average of 1 year (each cycle is 21 days))