Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Symptoms and General Pathology

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Carcinoma, Squamous Cell

Adenocarcinoma

Recurrence

Carcinoma, Adenosquamous

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Infective Agents

Analgesics

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Aldesleukin

Nivolumab

Interleukin-2

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Analgesics, Non-Narcotic

Tumor-infiltrating Lymphocyte Therapy (TIL) + Nivolumab Treatment Plan: Tumor harvest, Tumor-infiltrating Lymphocytes growth, 4 cycles of nivolumab, cytoreductive chemotherapy with cyclophosphamide and fludarabine, TIL infusion, Interleukin-2 treatment.

Tumor harvest for TIL growth in the lab: A sample of the participant's tumor will be collected and sent to the lab for TIL growth. TIL will be prepared and cryopreserved.

Tumor-infiltrating Lymphocytes (TIL)

Nivolumab will be administered intravenously at a fixed dose of 240 mg for 4 doses every 2 weeks prior to TIL. Nivolumab dose will be fixed at 480 mg every 4 weeks up to 12 months after TIL.

Cyclophosphamide will be administered at 60 mg/kg/day IV in 250 mL normal saline (NS) over approximately 2 hours. Cyclophosphamide will be initiated seven days prior to the anticipated TIL transfer, and the precise timing will depend on the rate of in vitro TIL growth. The dose will be based on the patient's body weight, but to prevent undue toxicity, it will not exceed a dose greater than 140% of the maximum ideal body weight per Metropolitan Life Insurance Company, Height and Weight Table.

After administration of Cyclophosphamide, Fludarabine will then be infused at 25 mg/m\^2 intravenous piggyback (IVPB) daily over approximately 30 minutes starting 5 days prior to TIL transfer. To prevent undue toxicity with fludarabine, the dose will be based on body surface area (BSA), but will not exceed a dose calculated on surface areas based on body weights greater than 140% of the maximum ideal body weight per Metropolitan Life Insurance Company Height and Weight Tables.

On day 0, all patients will receive TIL administered according to the current Moffitt Cell Therapy TIL Standard Operating Procedure (SOP). Eight (8) to twelve (12) hours after completing the TIL infusion, all participants will begin intermediate-dose decrescendo interleukin-2 (IL-2).

Tumor-infiltrating Lymphocyte Therapy

Interleukin-2 (IL-2) - a drug used to help the body's response to treatment on the immune system. A high dose regimen of IL-2 will be given after the infusion of the T-cells.

Interleukin-2 (IL2)

Ben Creelan, M.D.

Investigators plan to study the safety, side effects, and benefits of tumor-infiltrating lymphocytes (TILs) when they are given with the drug nivolumab. Nivolumab is a type of immunotherapy - a drug that is used to boost the ability of the immune system to fight cancer, infection, and other diseases.

In this study, these special immune T-cells will be taken from a sample of the participant's tumor tissue that will be surgically removed. Certain parts of these cells will be multiplied, or grown, in the laboratory, using the drug interleukin-2 (IL-2) during part of the process. They will then be given back to the participant by an infusion in their veins. These cells are called tumor- infiltrating lymphocytes (TILs). The use of TILs involves a combination of drugs, including the following:

* Fludarabine and cyclophosphamide - two types of chemotherapy drugs. These drugs will be used for what is called lymphodepletion. The purpose of lymphodepletion in this study is to temporarily reduce the number of normal lymphocytes circulating in the participant's body before they are given the TILs that were grown in the lab. This is so that there will be more "space" for the lymphocytes (TILs) that will be infused in their veins.
* Interleukin-2 (IL-2) - a drug used to help the body's response to treatment on the immune system. A high dose regimen of IL-2 will be given after the participant receives the infusion of the T-cells.

Nivolumab and Tumor Infiltrating Lymphocytes (TIL) in Advanced Non-Small Cell Lung Cancer

A Phase I Clinical Trial Combining Nivolumab and Tumor Infiltrating Lymphocytes (TIL) for Patients With Advanced Non-Small Cell Lung Cancer

Investigators plan to demonstrate that treatment with nivolumab in patients undergoing TIL therapy is safe with a continuous Pocock-type stopping boundary for serious toxicity of \< 17%, with safety reported based upon Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria. DLT defined as: any grade ≥3 immune-related adverse event definitely attributable to nivolumab. DLT related to adoptive cell therapy will be defined as a non-hematologic grade 4 or higher adverse event that is immediately life-threatening occurring upon or after the start of therapy that is immediately life-threatening and not related to non-small cell lung cancer or other pre-existing condition. Safety: Toxicity will be assessed within 4 weeks of the adoptive TIL transfer. The accrual will be halted if excessive numbers of participants with toxicity are seen. For example, if there are 5 or more out of 10 participants (full follow-up) with toxicity, the trial will be stopped.

Participants displaying objective response associated with the treatment regimen per Response Evaluation Criteria in Solid Tumors (RECIST v.1.1). The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.

Bristol-Myers Squibb

Prometheus Inc.

Stand Up To Cancer

Iovance Biotherapeutics, Inc.

H. Lee Moffitt Cancer Center and Research Institute

Adverse Events includes all enrolled patients who started initial nivolumab (20) but only 16 received TIL. Therefore the denominator (20) includes all enrolled patients exposed to any study tx. This table is intended to represent a summary-level overview for all patients enrolled on the trial, and not intended to indicate attribution, frequency, or causality for specific drugs or TIL. Please refer to the publication for dedicated adverse event tables, including grade

Nivolumab, 240 mg, IV infusion every 2 weeks for 8 weeks prior to Tumor Infiltrating Lymphocytes (TIL) infusion, and then after TIL infusion 480 mg every 4 weeks for up to 12 months

TIL+ Nivolumab

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Ben Creelan, MD

Rate of Dose Limiting Toxicity (DLT)

Confirmed

Unconfirmed

Number of Participants With Objective Response

Overall Study

Adenocarcinoma, Clear Cell

Disease Attributes

Pembrolizumab

Lenvatinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Recurrent clear cell carcinoma of gynecological origin (ovarian and endometrial primary) after progression on chemotherapy.

All patients will receive oral lenvatinib daily plus intravenous pembrolizumab 3-weekly.

A cycle is 21 days. Allowances will be made for stepwise dose reductions of lenvatinib due to treatment-related toxicities.

Toxicity will be assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, (CTCAE) Version 5.0.

Patients are planned to continue therapy until disease progression, intolerable toxicity, or withdrawal of patient consent.

pembrolizumab and lenvatinib

David Shao Peng Tan

This is a phase II non-randomized, multi-center study. The primary end point of this study is the objective response rate (ORR) at 24 weeks, using response evaluation criteria for solid tumors (RECIST) 1.1 criteria, for the combination therapy of continuous daily oral lenvatinib with three-weekly intravenous pembrolizumab in patients with recurrent clear cell carcinoma of gynecological origin (CCGC). The statistical design is Simon's minimax two-stage design and the present study aims to complete stage 1 of the Simon's two-stage design.

Primary Objective

(1) Objective: To determine the efficacy as measured by the objective response rate (ORR) at 24 weeks using RECIST 1.1 criteria when patients with recurrent CCGCs are treated with lenvatinib plus pembrolizumab.

Hypothesis: The ORR (complete response plus partial response) at 24 weeks seen in recurrent CCGC patients treated with lenvatinib plus pembrolizumab combination therapy will be improved compared to historical control (hypothesized ORR of 30% with combination therapy compared to historical ORR of ORR of 10% with chemotherapy).

Primary Endpoint: The ORR at 24 weeks using RECIST 1.1 criteria when patients with recurrent CCGCs are treated with lenvatinib plus pembrolizumab.

Secondary Objectives,

1. Objective: To determine the efficacy of lenvatinib plus pembrolizumab in recurrent CCGCs.

   Hypothesis: The ORR by immune RECIST (iRECIST) criteria, progression-free survival (PFS) rate and clinical benefit rate (CBR) (complete response plus partial response plus stable disease) at 24 weeks, as well as duration of response and PFS observed in recurrent CCGC patients treated with lenvatinib plus pembrolizumab combination therapy will be improved compared to historical control.

   Endpoint: To determine the ORR using iRECIST criteria at 24 weeks when patients with recurrent CCGCs are treated with lenvatinib plus pembrolizumab.

   Endpoint: To assess the duration of response when patients with recurrent CCGCs are treated with lenvatinib plus pembrolizumab.

   Endpoint: To assess the PFS when patients with recurrent CCGCs are treated with lenvatinib plus pembrolizumab.

   Endpoint: To determine the 24 week PFS rate of lenvatinib plus pembrolizumab in this population.

   Endpoint: To determine the CBR at 24 weeks of lenvatinib plus pembrolizumab in this population.
2. Objective: To describe the adverse event (AE) profile of lenvatinib plus pembrolizumab in this patient population.

Exploratory Objectives

1. Clinical Objectives: To evaluate the effect of potential prognostic factors (baseline patient and tumor characteristics, notably: initial performance status, stage at diagnosis and platinum-free interval), on the efficacy of lenvatinib plus pembrolizumab in this population.
2. Translational Objectives: To evaluate the pre- to post-treatment changes in the frequency of tumor-associated macrophages (TAMs) in patients receiving lenvatinib plus pembrolizumab.
3. Translational Objectives: To evaluate the pre- to post-treatment changes in the frequency and gene expression profile of different lymphocyte (e.g. CD4, CD8, Treg, B cells) and myeloid (e.g. DCs, MDSCs) subsets in patients receiving lenvatinib plus pembrolizumab.
4. Translational Objectives: To identify predictive biomarkers of response in patients receiving lenvatinib plus pembrolizumab (e.g. PD-1/PD-L1/VEGF expression).
5. Translational Objectives: To evaluate the pre-to post-treatment changes in the concentration of relevant cytokines/chemokines (e.g.: GM-CSF, G-CSF, VEGFA, IL2, IL12, IL13, IL6, Interferons) in patients receiving lenvatinib plus pembrolizumab.

combination therapy of continuous daily oral lenvatinib with three-weekly intravenous pembrolizumab in patients with recurrent clear cell carcinoma of gynecological origin (CCGC).

Trial of Lenvatinib Plus PembrolizumAb in Recurrent Gynecological Clear Cell Adenocarcinomas (LARA)

Phase II Trial of Lenvatinib Plus PembrolizumAb in Recurrent Gynecological Clear Cell Adenocarcinomas (LARA)

the percentage of subjects with a confirmed CR or PR as per RECIST 1.1 criteria.

time from enrolment to the first documented tumor progression, or death due to any cause whichever occurred first. PFS time of any living patient with no documented progression, or any patient starting other cytotoxic and/or cytostatic therapies, will be censored at the date of last evaluable disease assessment on-study. PFS time of patients with no evaluable disease assessment on-study will be censored at enrollment

This will be measured from the time measurement criteria for CR/PR (whichever is first recorded) are first met until the first date that recurrent or progressive disease is objectively documented.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nivolumab and Tumor Infiltrating Lymphocytes (TIL) in Advanced Non-Small Cell Lung Cancer	NCT03215810	Non-Small Cell ... Metastatic Non-... Squamous Cell C... Advanced NSCLC Adenosquamous C... Adenocarcinomas	Tumor-infiltrat... Nivolumab Cyclophosphamid... Fludarabine Tumor-infiltrat... Interleukin-2 (...	18 Years -	H. Lee Moffitt Cancer Center and Research Institute
Trial of Lenvatinib Plus PembrolizumAb in Recurrent Gynecological Clear Cell Adenocarcinomas (LARA)	NCT04699071	Adenocarcinomas Recurrent Gynec...	pembrolizumab a...	21 Years - 99 Years	National University Hospital, Singapore
Trial of Lenvatinib Plus PembrolizumAb in Recurrent Gynecological Clear Cell Adenocarcinomas (LARA)	NCT04699071	Adenocarcinomas Recurrent Gynec...	pembrolizumab a...	21 Years - 99 Years	National University Hospital, Singapore

Spots Global Cancer Trial Database for adenocarcinomas