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

NCT07130032 | Recruiting Phase 2

• 1 other identifier: 1.0
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

This study will evaluate efficacy and safety of anti-PD-1/PD-L1 antibodies combined with bevacizumab and metronomic cyclophosphamide in patients with metastatic non-small cell lung cancer (NSCLC) and cutaneous melanoma previously treated with immune checkpoint blockade (ICB). The hypotheses of this study are that a combination of ICB, cyclophosphamide, and bevacizumab prolongs progression-free survival and overall survival, and also increases rates of objective responses and disease control.

Conditions

Metastatic Non-small Cell Lung Cancer (NSCLC); Metastatic Cutaneous Melanoma

Keywords

Metastatic non-small cell lung cancer; Metastatic cutaneous melanoma; Immune checkpoint inhibitor; Bevacizumab; Metronomic cyclophosphamide

Outcome Measures

Primary Outcomes (3)

• Objective Response Rate (ORR) Per immune-related Response Evaluation Criteria in Solid Tumors (iRECIST)

  objective response rate (ORR) was defined as the proportion of participants whose best overall outcome included a confirmed complete response (CR) or partial response (PR). PR corresponds to a minimum 30% reduction in the total diameter of target lesions compared to the baseline measurements. CR indicates the total disappearance of all identified target lesions. Additionally, any pathological lymph nodes (classified as target or non-target) must shrink to a short axis measurement below 10 millimeters (mm).

  From randomization until the first documentation of best overall response (up to 24 months)

• Progression-free Survival (PFS) Per immune-related Response Evaluation Criteria in Solid Tumors (iRECIST)

  Progression-free survival (PFS) was defined as the time from randomization to the initial occurrence of documented disease progression (PD) or death from any cause, whichever occurs earlier. PD was characterized by at least a 20% enlargement in the total diameter of target lesions compared to the smallest sum recorded during the study, along with an absolute increase of 5 mm or more. The development of any new lesions was also classified as PD.

  From randomization until the first documentation of objective progression or death, whichever comes first (up to 24 months)

• Overall Survival (OS)

  Overall survival (OS) was measured as the duration (in months) from date of randomization to death resulting from any cause. Participants who had not experienced death by the time of data analysis were censored at their most recent confirmed date of survival.

  From randomization until the first documentation of objective progression or death, whichever comes first (up to 24 months)

Secondary Outcomes (3)

• Disease Control Rate (DCR) Per immune-related Response Evaluation Criteria in Solid Tumors (iRECIST)

  From randomization until the first documentation of objective progression or death, whichever comes first (up to 24 months)

• Duration of Response (DOR) Per immune-related Response Evaluation Criteria in Solid Tumors (iRECIST)

  From randomization until the first documentation of objective progression or death, whichever comes first (up to 24 months)

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs

  From start of study drug administration up to approximately 38 months

Study Arms (2)

NSCLC (n=60)

EXPERIMENTAL

The cohort of individuals with metastatic NSCLC will be treated with the reICB regimen (anti-PD(L)-1 antibodies+ cyclophosphamide+ bevacizumab) until disease progression or unacceptable toxicity.

Combination Product: reICB regimen (NSCLC)

melanoma (n=30)

EXPERIMENTAL

The cohort of individuals with metastatic cutaneous melanoma will be treated with the reICB regimen (anti-PD(L)-1 antibodies+ cyclophosphamide+ bevacizumab) until disease progression or unacceptable toxicity.

Combination Product: reICB regimen (melanoma)

Interventions

reICB regimen (NSCLC) COMBINATION_PRODUCT

* ICI (one of the following): Atezolizumab 1200 mg every 3 weeks/Nivolumab 240 mg every 2 weeks/Pembrolizumab 200 mg every 3 weeks * Cyclophosphamide 50 mg PO daily * Bevacizumab 7.5 mg/kg every 3 weeks

NSCLC (n=60)

reICB regimen (melanoma) COMBINATION_PRODUCT

* ICI (one of the following): Nivolumab 240 mg every 2 weeks/Pembrolizumab 200 mg every 3 weeks * Cyclophosphamide 50 mg PO daily * Bevacizumab 7.5 mg/kg every 3 weeks

melanoma (n=30)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• EuroCityClinic LLC: lead
• First Pavlov State Medical University in St. Petersburg, Russia: collaborator

Study Sites (1)

EuroCityClinic LLC

Saint Petersburg, Sankt-Peterburg, 197022, Russia

RECRUITING

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Melanoma

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Sergey V. Orlov, Professor

  EuroCityClinic LLC

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sergey V. Orlov, Professor

CONTACT

+79811957915; orloff-sv@mail.ru

Aram A. Musaelyan, PhD

CONTACT

+79990263455; a.musaelyan8@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PhD, medical onсologist

Study Record Dates

• First Submitted: August 14, 2025
• First Posted: August 19, 2025
• Study Start: August 14, 2025
• Primary Completion: August 14, 2025
• Study Completion (Estimated): December 1, 2027
• Last Updated: August 19, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share

Locations

RU (1)