Clinical Research Directory

Ivarmacitinib Combined With Camrelizumab and Apatinib for Unresectable Advanced Hepatocellular Carcinoma With Acquired Resistance to Immune Checkpoint Therapy: A Single-Arm Exploratory Clinical Study

Background： Hepatocellular carcinoma (HCC) stands as a formidable global health challenge. It ranks as the sixth most common malignant solid tumor worldwide and the third leading cause of cancer-related mortality. The disease is characterized by its insidious onset, rapid progression, and high recurrence rates, contributing to a dismal 5-year survival rate of approximately 18%. A critical factor in this poor prognosis is that nearly 57% of patients are diagnosed at an advanced stage, where curative surgical resection is no longer feasible. For these patients with unresectable advanced HCC (uHCC), effective systemic therapies are paramount to extend survival and improve quality of life. The advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis, has revolutionized the treatment landscape for numerous advanced cancers, including uHCC. These agents work by blocking the inhibitory signals that tumor cells exploit to evade immune surveillance, thereby reactivating cytotoxic T cells to attack the cancer. However, the clinical benefit of ICI-based therapies is not universal. A substantial proportion of patients-estimated between 15% to 40%-derive limited or no benefit. Primary resistance is defined as a lack of initial response, while acquired resistance refers to disease progression after an initial period of clinical benefit. There is no established, evidence-based standard of therapy for uHCC patients who progress following first-line ICI combination therapy, highlighting an urgent need for novel therapeutic approaches. The mechanisms underlying acquired resistance to ICIs are multifaceted and intricately linked to dynamic remodeling of the tumor immune microenvironment (TME). Several key pathways contribute: 1. Loss of Tumor Immunogenicity: Immune editing during treatment can select for tumor cell clones with low neoantigen expression, making them less visible to the immune system. 2. Immune Suppressive Cell Infiltration: The TME in resistant tumors often exhibits an accumulation of immunosuppressive cell populations, including regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). These cells create a profoundly inhibitory milieu that dampens anti-tumor T cell function. 3. T Cell Exhaustion: Persistent antigen exposure leads to a state of CD8⁺ T cell exhaustion, rendering them dysfunctional. These interconnected mechanisms collectively foster an immunosuppressive TME that allows tumors to evade ongoing immune attack, underscoring the need for combination strategies that can reshape the TME and re-sensitize tumors to immunotherapy. The JAK-STAT pathway serves as a critical signaling hub for numerous cytokines and growth factors, playing a pivotal dual role in immunity and inflammation. In the context of HCC and ICI resistance, its activation is particularly relevant: 1. Pathway Activation in HCC: The JAK/STAT pathway is ubiquitously activated in both primary and recurrent HCC tumors and contributes to the proliferation and survival of tumor-initiating cells. 2. Driver of an Immunosuppressive TME: Hyperactivation of this pathway, often via cytokines like IL-6, promotes the recruitment and activation of immunosuppressive MDSCs and M2-polarized TAMs. It also contributes to T cell exhaustion. 3. Preclinical and Clinical Proof-of-Concept: In preclinical models, JAK/STAT inhibition has been shown to reduce MDSC infiltration and restore T cell function. Most compellingly, recent clinical studies in other cancer types published in high-impact journals like Science (2024) have demonstrated that adding a JAK inhibitor to PD-1 blockade can re-sensitize tumors and yield significant clinical responses in patients who had developed resistance to immunotherapy alone Purpose: This single-arm, exploratory clinical study aims to evaluate the efficacy and safety of Ivarmacitinib (a selective JAK1 inhibitor) combined with Camrelizumab (anti-PD-1) and Apatinib (anti-VEGFR2) in patients with advanced unresectable HCC who have progressed after first-line ICI-based combination therapy. Methods: This study plans to enroll 65 patients with advanced unresectable hepatocellular carcinoma (unresectable BCLC stage B or stage C) who have been clinically or pathologically diagnosed, have previously received at least 4 cycles of guideline-recommended first-line targeted therapy combined with PD-1/PD-L1 immunotherapy, achieved a partial response, but subsequently experienced disease progression confirmed by RECIST 1.1 criteria after at least 4 cycles (indicating acquired resistance). All enrolled patients will receive triple therapy consisting of Ivarmacitinib + Apatinib + Camrelizumab. Treatment will continue until disease progression, unacceptable toxicity, or for up to 2 years.

Sintilimab Plus Anlotinib as Second or Further-line Therapy for ES-SCLC Who Have Progressed After Anti-PD-1/L1 Therapy

The phase II study enrolled ES-SCLC patients who had disease progression after anti-PD-1/L1 therapy. Participants received intravenous sintilimab 200 mg on day one and oral daily anlotinib 8-12 mg on days 1-14 once every three weeks per cycle. The primary endpoint was objective response rate (ORR). The secondary endpoints included overall survival (OS), progression-free survival (PFS) , disease control rate (DCR) and safety.

Intestinal Low Dose Radiotherapy Combined With Immunotherapy in Immune-resistant Metastatic Solid Tumors

Preclinical and clinical studies have shown that intestinal low dose radiotherapy (ILDR) can enhance antitumor immunity and response to immune checkpoint blockade (ICB). Therefore, the investigators launch a phase Ⅱ trial to evaluate the clinical value of combining ILDR and programmed cell death-1/ -ligand 1 (PD-1/PD-L1) inhibitors in patients with ICB refractory metastatic solid tumor. This study is designed as a researcher-initiated, two-stage and prospective clinical trial. The target population is patients with advanced metastatic malignant solid tumors who have progressed after immunotherapy. The primary endpoints include objective response rate (ORR), disease control rate (DCR), progression free survival while receiving ILDR combined therapy (PFS2), and lesion-based abscopal response rate. The secondary endpoints include incidence of adverse events (AEs), cancer-specific survival (CSS), and overall response rate (OS). In the treatment stage Ⅰ, sixteen subjects will be enrolled in this trial. The primary objective of this stage is to evaluate the safety and efficacy of 1Gy ILDR combined with PD-1/PD-L1 inhibitors in immune-resistant metastatic malignant solid tumors, and biomarker exploration for response prediction. The inclusion criteria, exclusion criteria and sample size for treatment stage Ⅱ will be modified on the basis of results from Stage Ⅰ. The objective of the stage Ⅱ is to determine effects and safety of various dosage regimen of ILDR combined with PD-1/PD-L1 inhibitors in target patients. Eligible patients will be subjected to 1-3Gy ILDR. Tumor response will be assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as well as Immune related RECIST (iRECSIST). The extent or severity of adverse reactions will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0). Furthermore, tissue samples, stool samples, and peripheral blood samples will be collected for biomarker exploration.

PD-1 Combined With Bevacizumab and PCSK-9 Inhibitor in Patients With Advanced NSCLC Who Have Progressed After Anti- PD- 1/L1 Therapy

This study evaluated the sintilimab combination of bevacizumab and tafolecimab in NSCLC patients who have previously been treated with anti- PD- 1/ligand (L)1 and acquired resistance. The patients were assigned to receive sintilimab(200mg Q3W) in combination with bevacizumab(7.5mg/kg Q3W) and tafolecimab(600 mg Q6W). The primary endpoints of the study were progression- free survival (PFS) assessed by RECISTv1.1 , while secondary endpoints included objective response rate (ORR), and overall survival (OS) and safety.