Anti-PD-1/PD-L1 with bevacizumab and low-dose cyclophosphamide for metastatic NSCLC and cutaneous melanoma after prior checkpoint therapy

A Trial To Compare Efficacy And Safety Of Anti-PD-1/PD-L1 Antibodies In Combination With Bevacizumab And Metronomic Cyclophosphamide In Patients With Non-Small Cell Lung Cancer And Cutaneous Melanoma Previously Treated With Immune Checkpoint Blockade

We will try giving anti-PD-1/PD-L1 drugs together with bevacizumab and continuous low-dose cyclophosphamide to people with metastatic NSCLC or cutaneous melanoma whose cancer progressed after prior immune checkpoint treatment.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 90 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: EuroCityClinic LLC (network)
• Drugs / interventions: chemotherapy, radiation, bevacizumab, cyclophosphamide, immunotherapy
• Locations: 1 site (Saint Petersburg, Sankt-Peterburg)
• Trial ID: NCT07130032 on ClinicalTrials.gov

What this trial studies

This is a phase 2 interventional trial testing a combination of anti-PD-1/PD-L1 antibodies with bevacizumab and metronomic (continuous low-dose) cyclophosphamide in patients with metastatic non-small cell lung cancer or cutaneous melanoma who previously received immune checkpoint blockade. The regimen aims to overcome acquired resistance to PD-1/PD-L1 therapy by normalizing tumor vasculature (bevacizumab) and altering the tumor immune environment through low-dose cyclophosphamide effects on regulatory and myeloid cells. Key outcomes include progression-free survival, overall survival, objective response rate, and safety. The trial is being conducted at EuroCityClinic in Saint Petersburg, Russia, with academic collaboration from First Pavlov State Medical University.

Who should consider this trial

Good fit: Adults (≥18) with metastatic NSCLC or cutaneous melanoma who previously received anti-PD-1/PD-L1 immune checkpoint therapy, have ECOG 0-2, and lack excluded driver mutations (for NSCLC, e.g., EGFR/ALK/ROS1/RET) are the intended candidates.

Not a fit: Patients with active autoimmune disease requiring immunosuppression, poor performance status (ECOG >2), or NSCLC with excluded oncogenic driver mutations are unlikely to receive benefit from this regimen.

Why it matters

Potential benefit: If successful, the combination could extend progression-free and overall survival and increase tumor response rates in patients who stopped responding to prior checkpoint inhibitors.

How similar studies have performed: Other trials combining PD-1/PD-L1 blockade with anti-VEGF therapy have shown improved response rates and PFS in cancers such as NSCLC, renal cell carcinoma, and hepatocellular carcinoma, while the specific addition of metronomic cyclophosphamide is less well established.

Eligibility criteria

Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Provide written informed consent
* Age ≥ 18 years
* Histologically confirmed diagnosis of NSCLC and cutaneous melanoma with distant metastases.
* No mutations in the EGFR gene, ALK, ROS1, RET gene translocations (in case of NSCLC).
* For NSCLC: the individuals had previously received anti-PD-(L)1 antibodies in combination with platinum-containing chemotherapy either in the first line or sequentially in the first and second lines for the treatment of metastatic disease.
* For NSCLC: the individuals had previously received anti-PD-(L)1 antibodies for \>6 months and experienced disease progression.
* For cutaneous melanoma: the individuals had previously received anti-PD-1 antibodies either in combination with or without anti-CTLA4 therapy for metastatic disease. If the patient had the BRAF V600 mutation, they were also treated with BRAF and MEK inhibitors.
* For cutaneous melanoma: the patient has previously received anti-PD-1 antibodies with or without anti-CTLA4 therapy for metastatic disease for \>6 months and experienced disease progression

Exclusion Criteria:

* Presence of clinically significant cardiovascular disease: severe or unstable ischemic heart disease, history of myocardial infarction, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias.
* Stroke and/or transient ischemic attack within 6 months prior to screening;
* Uncontrolled hypertension
* History of previous malignancies except non-melanoma skin cancers, or in situ cervical or breast cancer unless a complete remission was achieved at least 2 years prior to randomization AND no additional therapy is required during the study period. Patients having hepatic involvement of cancer should be excluded as per investigator assessment.
* Patients with CNS metastases are eligible only if the metastases are adequately treated.
* Absolute neutrophil count (ANC) \<1.5×109/L, platelet count \<100×109/L, or hemoglobin \<9.0 g/dL.
* Serum total bilirubin \>1.5 × the upper limit of normal (ULN). Participants with Gilbert syndrome, bilirubin \<2 X ULN, and normal AST/ALT are eligible;
* Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3 × ULN;
* Serum creatinine \>1.5 × ULN.
* History of a thromboembolic event
* Presence of any allergic reactions to components of the study drugs
* Concomitant medications with a known risk of causing QT prolongation and/or Torsades de Pointes.
* Any parallel anti-cancer systemic therapy, radiation therapy
* Women who are pregnant or lactating;
* Presence of unresolved adverse events of grade 2 or higher toxicity, according to CTCAE v5.0 criteria, from prior therapy (except for alopecia or neurotoxicity grade≤2).
* Any other serious or uncontrolled medical disorder, active infection, physical examination finding, laboratory finding, altered mental status, or psychiatric condition that, in the opinion of the investigator, would limit a patient's ability to comply with the study requirements, substantially increase risk to the patient, or impact the interpretability of study results.

Where this trial is running

Saint Petersburg, Sankt-Peterburg

• EuroCityClinic LLC — Saint Petersburg, Sankt-Peterburg, Russia (RECRUITING)

Study contacts

• Principal investigator: Sergey V. Orlov, Professor — EuroCityClinic LLC
• Study coordinator: Sergey V. Orlov, Professor

Conditions: Metastatic Non-small Cell Lung Cancer, Metastatic Cutaneous Melanoma, Metastatic non-small cell lung cancer, Metastatic cutaneous melanoma, Immune checkpoint inhibitor, Bevacizumab, Metronomic cyclophosphamide