NCT05440864Phase 2Recruiting
University Health Network, Toronto · University Health Network, Toronto, Ontario
Hepatocellular Carcinoma (HCC) is the third most common cause of death from cancer world wide and the incidence is rising globally. Despite surgical resection in appropriate patients, many patients recur.
The results of the IMbrave150 study have established PD-L1 inhibition in combination with VEGF inhibition as a new standard of care highlighting the role of immune checkpoint inhibition in advanced HCC. In addition, the combination of Tremelimumab and Durvalumab has demonstrated efficacy in advanced HCC; the HIMALAYA trial has now completed accrual in treatment naïve patients with advanced HCC. Furthermore the earlier use of immune checkpoint inhibitors in this disease are being explored with adjuvant combination strategies, including the EMERALD-2 trial (NCT03847428). Neoadjuvant treatment in HCC allows for delivery of treatment pre surgery and may enhance pathological responses and improve outcomes. The delivery of combination CTLA-4 and PD-L1 inhibition has demonstrated efficacy in other tumour types in the neoadjuvant setting where the impact on the tumour microenvironment has also been evaluated. The safety and feasibility of Durvalumab and Tremelimumab in resectable HCC has yet to be established.
Hypotheses Pre-operative (pre-op) Durvalumab and Tremelimumab treatment is safe and feasible in pre surgical setting for upfront resectable HCC The combination of Durvalumab and Tremelimumab pre-op will result in changes in immune and molecular characteristics within the tumour microenvironment.
Overall Study Design This is a phase II, open-label multi-centre study to assess safety of Durvalumab and Tremelimumab treatment in pre-op setting for upfront resectable HCC, followed by adjuvant Durvalumab.
28 patients are expected to enrol at three sites. Patients will receive pre-op: 1 dose Tremelimumab (300mg) (T300) with Durvalumab (1500mg) at cycle 1 and 1 further cycle of Durvalumab (1500mg) only. Post-surgical resection, adjuvant therapy will consist of Durvalumab Q4W for up to a maximum of 12 months in total or 13 cycles of Durvalumab (11 cycles post op).
All participants will be treated until progressive disease or unacceptable toxicity or withdrawal of consent or another discontinuation criterion is met. All participants will be followed for survival until the end of study.
No dose reductions of Tremelimumab and Durvalumab will be allowed. Statistics The primary objective of this study is to assess safety of pre-op treatment with Durvalumab and Tremelimumab.
For safety, with the null proportion of patients who discontinue treatment due to AEs, imAEs or SAE is 30% versus the alternative proportion is 10% or less than 10%, a sample size of 28 provides 80% power to detect the proportion difference with a two-sided alpha level of 0.1.
The sample size estimate is based on the two-sided exact test for binomial proportion considering Binomial Enumeration method.
Eligibility: 18 Years to · All · For inclusion in the study, patients should fulfil the following criteria at time of study enrolment or when indicated:
1. Patient must be capable of providing written informed consent.
2. Age \>18 years at time of study entry
3. Histologically proven resectable HCC (early and intermediate stage HCC)\*
4. Must consent to provide biopsy sample prior to treatment
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
6. Childs Pugh score of 5 or 6
7. ALBI grade 1†
8. Patients with HBV infection, which is characterized by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA (≥10 IU/ml or above the limit of detection per local lab standard), must be treated with antiviral therapy, as per institutional practice, to ensure adequate viral suppression (HBV DNA ≤2000 IU/mL) prior to study entry. Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication. Patients who test positive for anti-hepatitis B core (HBc) with undetectable HBV DNA (\<10 IU/ml or under limit of detection per local lab standard) do not require anti-viral therapy prior to study entry. These subjects will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥10 IU/ml or above the limit of detection per local lab standard). HBV DNA detectable subjects must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication.
9. Patients with HCV infection must have management of this disease per local institutional practice throughout the study. HCV diagnosis is characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody upon enrollment.
10. Evidence of post-menopausal status or negative serum pregnancy test for female pre-menopausal patients.
11. Female of childbearing potential and non-sterilized male partners of a female patient of childbearing potential must agree to use effective method of contraception from the time of screening throughout the total duration of the drug treatment and 6 months after the last dose of study treatment. (See exclusion #22 for definition of effective method of contraception).
12. Adequate normal organ and marrow function as defined below within screening period:
* Haemoglobin ≥9.0 g/dL
* Absolute neutrophil count (ANC ≥1.0 × 109 /L)
* Platelet count ≥65 × 109/L
* Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). \<\<This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
* AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal
* Measured creatinine clearance (CL) \>40 mL/min or Calculated creatinine clearance CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
Males:
Creatinine CL (mL/min) = Weight (kg) x (140 - Age) / 72 x serum creatinine (mg/dL)
Females:
Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 / 72 x serum creatinine (mg/dL)
\- Albumin ≥2.8g/dl
\- International normalized ratio ≤1. (for patients receiving Warfarin, please consult with the study physician)
13. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
14. Body weight \> 30kg
NCT05844046Phase 2Recruiting
Enrico De Toni · Hospital of the University of Munich, Munich
This is a randomized, open-label, multi-center, international, Phase II study to assess the efficacy and safety of sequential or up-front triple treatment with durvalumab, tremelimumab and bevacizumab for non-resectable hepatocellular carcinoma.
Patients will be randomized in a 1:1 ratio to one of the following arms:
Arm A: initial treatment with durvalumab plus tremelimumab followed by treatment escalation with the addition of bevacizumab upon radiological progression or in the absence of objective response
Arm B: up-front treatment with durvalumab, tremelimumab and bevacizumab
Patients will be stratified according to macrovascular invasion and etiology of liver disease (viral etiologies versus others).
Eligibility: 18 Years to · All · KEY INCLUSION CRITERIA
Age ≥18 years at the time of study entry
Confirmed HCC based on histopathological findings from tumor tissues.
Must not have received prior systemic therapy for HCC.
Not eligible for locoregional therapy for unresectable HCC. For patients who progressed after locoregional therapy for HCC, locoregional therapy must have been completed ≥28 days prior to the baseline scan for the current study.
Barcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for locoregional therapy) or stage C
Child-Pugh Score class A
ECOG performance status of 0 or 1 at enrollment
At least 1 measurable lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have a short axis ≥15 mm) with computerized tomography (CT) or magnetic resonance imaging (MRI), and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines. A lesion which progressed after previous ablation or TACE could be measurable if it meets these criteria.
Adequate organ and marrow function
KEY EXCLUSION CRITERIA
Previous study drug(s) assignment in the present study.
Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 28 days of the first dose of study drug(s).
Major surgical procedure or significant traumatic injury within 28 days prior to the first dose of study drug(s), abdominal surgery, abdominal interventions, or significant abdominal traumatic injury within 60 days prior to randomization
History of allogeneic organ transplantation (eg, liver transplant).
History of hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy
Clinically meaningful ascites
Patients with main portal vein thrombosis (i.e., thrombosis in the main trunk of the portal vein, with or without blood flow) on baseline imaging.
Patient currently exhibits symptomatic or uncontrolled hypertension
Active or prior documented autoimmune or inflammatory disorders, diverticulitis. Patients without active disease in the last 5 years are excluded unless discussed with the Study Physician and considered appropriate for study participation.
Patients co-infected with HBV and HCV, or co-infected with HBV and hepatitis D virus (HDV).
History of another primary malignancy except for the exceptions defined by the study protocol.
Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart).
Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
History of active primary immunodeficiency.
Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug(s). Note: Patients, if enrolled, should not receive live vaccine while receiving study drug(s) and up to 30 days after the last dose of study drug(s).
Major gastrointestinal bleeding within 4 weeks prior to randomization.
Patients with untreated or incompletely treated varices with bleeding or high-risk for bleeding. Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed and treated per local standard of care prior to enrollment. Patients who have undergone an EGD within 6 months prior to randomization do not need to repeat the procedure. Those who have received banding and/or sclerotherapy and with no bleeding event within the prior 6 months are eligible provided that a re-endoscopy is performed and that varices remained obliterated, minimal or Grade I
Significant vascular disease including aortic aneurysm requiring surgical repair or peripheral arterial thrombosis with 6 months prior to randomization
History of abdominal or tracheoesophageal fistula or gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization.
Evidence of bleeding diathesis or significant coagulopathy
Severe, nonhe
NCT06492421Phase 2Recruiting
Second Affiliated Hospital of Guangzhou Medical University · The Second Affiliated Hospital of Guangzhou Medical University, Guanzhou, Guangdong
This phase II trial studies how well intra-tumor injection of double checkpoint inhibitors work when given alone and in combination with chemotherapy or/and bevacizumab in treating patients with previously untreated stage I-IIIA non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as ipilimumab, pembrolizumab or durvalumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Drugs used in interventional radiological chemotherapy, such as idabubicin, can directly kill the cancer cell and release tumor antigens to activate DC function in situ. Giving intra-tumor injection of checkpoints inhibitors with or without chemotherapy and/or bevecizumab may work better than in vein infusion of the drugs in treating patients with non-small cell lung cancer.
Eligibility: 18 Years to 75 Years · All · 1. Histologically or cytologically confirmed previously untreated non-small cell lung cancer. If a diagnostic biopsy is available, a pre-treatment biopsy is not required. Patients with a suspected lung cancer are eligible, but pathology must be confirmed prior to initiating treatment on study.
2. Patients with stage IIIA must not have more than one mediastinal lymph node station involved by tumor.
3. All patients must have lymph node evaluation of contralateral stations 2 and/or 4 to exclude N3 disease.
4. The patient must be a suitable candidate for surgery, in the opinion of the treating physician.
5. Signed and dated written informed consent must be provided by the patient prior to admission to the study in accordance with International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guidelines and to the local legislation.
6. Eastern Cooperative Oncology Group (ECOG) performance status score 0-1.
7. Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L; Hemoglobin \>= 8.0 g/dL; Platelets \>= 100 x 10\^9/L; Total bilirubin =\< 1.5 x upper limit of normal (ULN) (except subjects with Gilbert syndrome who can have total bilirubin \< 3.0 mg/dL); Creatinine =\< 1.5 x ULN or calculated creatinine clearance \>= 50 mL/min using Cockcroft-Gault formula for creatinine clearance calculation OR 24-hour urine creatinine clearance \>= 50 mL/min.
NCT07759856Phase 2Recruiting
Tianjin First Central Hospital · Tianjin First Central Hospital, Tianjin, Tianjin Municipality
This research study is designed for patients with extensive-stage small cell lung cancer (ES-SCLC) who have already received four cycles of standard chemotherapy, with at least two cycles combined with immunotherapy, and have achieved disease control (stable disease, partial response, or complete response) at their last efficacy evaluation.
In this study, participants will be randomly assigned to one of two groups:
Group A will receive standard immunotherapy plus 1 to 3 courses of allogeneic natural killer (NK) cell therapy. Each course consists of six NK cell infusions given over 28 days.
Group B will receive standard immunotherapy alone. All participants will continue treatment until their disease progresses or they experience unacceptable side effects. The immunotherapy agents used in this study are those recommended by major international and national clinical guidelines for extensive-stage SCLC, including but not limited to durvalumab, atezolizumab, serplulimab, and adebrelimab.
The purpose of this study is to evaluate whether adding NK cell therapy to standard immunotherapy can provide additional benefits for patients with extensive-stage SCLC who have responded well to initial treatment.
Eligibility: 18 Years to · All · * 1: Male or female, aged 18 years or above
2: ECOG score 0-2
3: metastatic or extensive-stage small cell lung cancer (SCLC) confirmed by histology or cytology, followed by 4 cycles of platinum-based doublet-chemotherapy with at least 2 cycles of immune checkpoint inhibitor plus chemotherapy. And stable disease (SD), partial response (PR), or complete response (CR) as assessed by imaging (RECIST1.1 criteria) after the last treatment. (The checkpoint inhibitors used were those recommended by the NCCN, ESMO, and CSCO guidelines for extensivestage SCLC, including but not limited to: Duvalumab, atezolizumab, slulizumab, adbelimumab, toripalimab, etc.)
4: After standard concurrent chemoradiotherapy, LS-SCLC could be enrolled in this study if sensitive relapse (relapse more than 6 months after the end of first-line treatment) progressed to extensive-stage (Ed) and met the inclusion criteria No.3;
5: At least 4 weeks after major surgery or trauma, and the wound must be completely healed; At least 1 week after minor surgical procedures or trauma (e.g., tissue biopsy or fine-needle aspiration);
6: Objective measurable lesions according to RECIST 1.1 criteria;
7: predicted survival time ≥1 year;
8: bone marrow function: ANC≥1.5×109/L, HB≥70 g/L (blood transfusion allowed), PLT≥80×109/L;
9: Liver function: ALT≤3×ULN, AST≤3×ULN, TBIL≤2×ULN (patients with liver metastasis ALT≤5×ULN, AST≤5×ULN, TBIL≤2×ULN) Child-Pugh score ≤7; Renal function: uric acid \<500 μmol/L, serum creatinine \<1.7 mg/dL, proteinuria ≤2+ or ≤2g/24h, glomerular filtration rate (GFR) ≥60 ml/min/1.73m2;
10: no history of autoimmune diseases or current autoimmune diseases;
11: The subjects voluntarily participated in the study, signed the informed consent form, communicated well with the investigators, and completed the study in accordance with the protocol.
NCT06830694Phase 2Recruiting
Sehhoon Park · Samsung Medical Center, Seoul, Gangnam-gu
The primary treatment option for non-small cell lung cancer (NSCLC) adenocarcinoma (ADC) with activating epidermal growth factor receptor (EGFR) mutation is EGFR tyrosine kinase inhibitor (TKI). After a certain period of treatment with EGFR TKI, acquired resistance emerges most frequently with a secondary mutation, p.T790M (36-50%), followed by MET amplification (10-19%). Interestingly, up to 3-5% of patients experience histological transformation into small cell lung cancer (SCLC).
As an underlying mechanism, ADC with a predisposed clonally inactivated Rb and p53 mutation and APOBEC mutation signature is known to be associated with SCLC transformation. The transformed SCLC harbors similar morphological and immunohistochemical (IHC) characteristics as those observed in de novo SCLC, including high expression of chromogranin and synaptophysin. However, little is known about the clinical outcomes of transformed SCLC, with limited studies arguing that their outcomes are similar to those of de novo SCLC, where the median overall survival is approximately 9 to 10 months after the transformation.
As the first line treatment of SCLC, atezolizumab or durvalumab with four cycles of conventional chemotherapy followed by maintenance therapy demonstrated prolonged overall survival (OS) and placed as the standard treatment option. However, median progression-free survival (PFS) of both study was only 5.2 months and 5.1 months, despite the objective response rate showing 60.2% and 79%. This finding suggest further development of maintenance treatment strategy to prolonged longer duration of response to the treatment.
In addition to the conventional treatment, Tarlatamab (AMG757), bispecific t-cell engager (BiTE), designed to engage DLL3 on SCLC and CD3 on T-cell has been tested in SCLC. DLL3 is expressed in more than 80% of patients with SCLC, regardless of disease stage and researched for the potential target protein for the antibody based treatment in SCLC. By targeting DLL3 using Tarlatamab, engagement of tumor antigen and CD3 lead to cytotoxic synapse formation, triggering the release of proinflammatory cytokines, perforin, and granzymes from activated T-cells, potentially resulting apoptosis. The first clinical outcome of Tarlatamab was reported from the DeLLphi-300 study, phase 1 dose exploration study, showing confirmed partial response in 23% of the heavily treated SCLC and 37% of the patients showed decrease in tumor burden. Median duration of response was 13.0 months (95% confidential interval CI: 6.2 - 14.9 months), median PFS of 3.7 months and median OS was 13.2 months. In the treatment naïve SCLC, DeLLphi-303 study, phase 1b study combining tarlatamab + PD-L1 inhibitor + carboplatin and etoposide, is ongoing to evaluate the clinical efficacy in the front line setting which include only histologically confirmed extensive disease SCLC population (NCT05361395).
Based on previous clinical and pre-clinical outcomes, showing similar disease characteristics between transformed SCLC from the adenocarcinoma who treated with EGFR TKI with de novo SCLC, this study is designed to evaluate the clinical efficacy of tarlatamab with currently standard treatment in transformed SCLC.
Eligibility: 19 Years to · All · 1. Histologically confirmed SCLC and no prior systemic treatment for SCLC
2. Patient initially diagnosed with activating EGFR mutation (L858R, Del 19) and treated with any kind of EGFR TKI.
3. Confirmed SCLC transformation right after EGFR TKI treatment failure.
4. Age ≥19 years
5. ECOG performance status of 0 to 1
6. Had at least one measurable lesion.
7. Adequate organ function
* Absolute neutrophil count ≥ 1.5 x 109/L
* Platelet count ≥ 100 x 109/L
* Hemoglobin ≥ 9 g/dL
* Estimated glomerular filtration rate based on Modification of Diet in Renal Disease calculation \> 30 mL/min/1.73 m2
* Aspartate aminotransferase and alanine aminotransferase ≤ 3 x upper limit of normal (ULN) (or ≤ 5 x ULN for subjects with liver involvement)
* Total bilirubin ≤ 1.5 x ULN (or ≤ 2 x ULN for subjects with liver metastases)
* Prothrombin time (PT)/international normalized ratio and partial thromboplastin time or activated partial thromboplastin time ≤ 1.5 x institutional ULN Note: Subjects on stable anticoagulation therapy are allowed.
8. Pulmonary function: No clinically significant pleural effusion at the timepoint of screening. Pleural effusion with no significant symptom is allowed for enrollment.
9. Cardiac function: Cardiac ejection fraction ≥ 50%
10. Female subjects must either be of non-reproductive potential
11. Female subject with reproductive potential can be enrolled with agreement to following guidance.
* subject uses contraception during treatment and through 60 days after receiving last dose of tarlatamab or for 6 months after last dose of carboplatin and/or etoposide and 5 months after last dose of atezolizumab.
12. Subject is willing and able to comply with the protocol
13. Signed written informed consent
