Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Rare Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Carcinoma, Small Cell

Small Cell Lung Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Small Cell Lung Cancer

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Ipilimumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

During Treatment Part A nivolumab 240 mg IV q2w as monotherapy is administered. At the time of disease progression a re-biopsy is performed before initiation of combination therapy (Treatment Part B). Within Treatment Part B, nivolumab is given in a dose of 3 mg/kg q2w together with ipilimumab 1 mg/kg IV q6w.

Within Treatment Part A, nivolumab 1 mg/kg q3w together with ipilimumab 3 mg/kg q3w for a total of four doses is administered. After the four combined doses have been administered, a re-biopsy is performed before initiation of Treatment Part B. In Treatment Part B, nivolumab 240 mg q2w monotherapy is administered until disease progression or unacceptable toxicity

Cohort 1: addition of ipilimumab in case of progression on nivolumab monotherapy.

Nivolumab, Ipilimumab

Cohort 2: upfront combination therapy of nivolumab and ipilimumab for four cycles, followed by nivolumab monotherapy.

Jürgen Wolf, MD

BIOLUMA is a multicentric non-randomised phase II trial in patients with non-squamous non-small cell lung cancer (NSCLC) (Cohort 1) and patients with small-cell lung cancer (SCLC) (Cohort 2) after failure of platinum-based first-line therapy. NSCLC patients are treated with nivolumab until disease progression and subsequently receive a combination therapy of nivolumab and ipilimumab. SCLC patients receive four cycles of nivolumab in combination with ipilimumab and subsequent nivolumab monotherapy. Primary endpoint for both cohorts is overall response rate of combination therapy.

Within the diagnostic part tumor biopsies will be analysed. Tumor tissue will be obtained before initiation of therapy and after progression on nivolumab monotherapy before addition of ipilimumab in Cohort 1 and after completion of the four nivolumab/ipilimumab combination cycles before continuation of nivolumab monotherapy in Cohort 2, respectively. Flow cytometry of blood samples and microbiome analysis of deep rectal swaps are performed prior to therapy as well as during course of treatment.

Cohort 1 (NSCLC) is closed for enrollment due to Sponsor decision.

In Cohort 2 (SCLC) a prescreening for high Tumor Mutation Burden is necessary before enrollment.

Cohort 2 (SCLC) has been subdivided by amendment in Cohort 2a without prescreening and Cohort 2b with TMB-prescreening. For Cohort 2a enrollment has been stopped in December 2017. Cohort 2b is closed for enrollment as the cohort is fully recruited.

The treatment period is subdivided in Treatment Part A and B which differ between the two cohorts:

Cohort 1 (non-squamous NSCLC):

During Treatment Part A nivolumab 240 mg IV q2w as monotherapy is administered. At time of disease progression another re-biopsy is mandatory before initiation of combination therapy (Treatment Part B). Within Treatment Part B, nivolumab is given in a dose of 3 mg/kg q2w together with ipilimumab 1 mg/kg IV q6w.

Cohort 2 (SCLC):

Patients have to undergo a prescreening for high Tumor Mutation Burden. Within Treatment Part A, nivolumab 1 mg/kg q3w together with ipilimumab 3 mg/kg q3w for a total of four doses is administered. After the four combined doses have been administered, another re-biopsy is mandatory before initiation of Treatment Part B. In Treatment Part B, nivolumab 240 mg q2w monotherapy is administered until disease progression or unacceptable toxicity.

BIOLUMA: Biomarkers for Nivolumab and Ipilimumab and Evaluation of the Combination in Lung Cancer

A Phase II Trial of Nivolumab in Combination With Ipilimumab to Evaluate Efficacy and Safety Relapsed in Lung Cancer and to Evaluate Biomarkers Predictive for Response to Immune Checkpoint Inhibition

ORR is defined as proportion of patients with reduction in tumor burden as assessed by RECIST 1.1 criteria (investigator-assessed).

Time from date of first dose to the date of death to any cause.

Time from the date of first dose to first documentation of objective disease progression or to death on study due to any cause, whichever occurs first.

Time from the first documentation of objective tumor response (CR or PR) that is subsequently confirmed to the first documentation of objective disease progression or to death due to any cause, whichever occurs first

Adverse events are documented according to the Common Terminology Criteria for Adverse Events (CTCAE)

Serious adverse events are documented according to the Common Terminology Criteria for Adverse Events (CTCAE)

Bristol-Myers Squibb

Lung Cancer Group Cologne

Digestive System Diseases

Carcinoma, Hepatocellular

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Immunomodulating Agents

All enrolled subjects will receive nivolumab 3 mg/kg plus ipilimumab 1 mg/kg intravenously on day 1 of each cycle (every 3 weeks). Tumor assessment will be done after 6 weeks (2 cycles) and 12 weeks (4 cycles).

nivolumab, ipilimumab

Bor-Rong Chen, BS

Chiun Hsu, MD, PhD

Yan-Shen Shan, MD, PhD

Chia-Jui Yen, MD, PhD

Yih-Jyh Lin, MD

Tsung-Ching Chou, MD

Li-Tzong Chen, MD, PhD

Ying-Jui Chao, MD

Ting-Tsung Chang, MD

Nai-Jung Chiang, MD, PhD

Kwang-Yu Chang, MD, PhD

Hui-Jen Tsai, MD, PhD

Shang-Hung Chen, MD, PhD

Yung-Yeh Su, MD

Rey-Heng Hu, MD, PhD

Ming-Chih Ho, MD, PhD

Yao-Ming Wu, MD, PhD

Cheng-Maw Ho, MD

Ann-Lii Cheng, MD, PhD

Chih-Hung Hsu, MD, PhD

Zhong-Zhe Lin, MD, PhD

Ying-Chun Shen, MD, PhD

Yu-Yun Shao, MD, PhD

Li-Chun Lu, MD

Chien-Hung Chen, MD, PhD

Bang-Bin Chen, MD, MS

Ja-Der Liang, MD, PhD

Tai-Chung Tseng, MD, PhD

Sih-Han Liao, MD

Jian-Zhi Dong, MD

Tsung-Hao Liu, MD

Jiunn-Chang Lin, MD, PhD

Tsang-En Wang, MD

Tun-Sung Huang, MD

Yi-Fang Chang, MD, PhD

Nei-Wen Sue, MD, PhD

Ching-Wei Chang, MD, PhD

Ya-Ting Jan, MD

Yee Chao, MD, PhD

Gar-Yang Chau, MD, MPH

Hao-Jan Lei, MD

Shu-Cheng Chou, MD

Chung-Pin Li, MD, PhD

Yi-Hsiang Huang, MD, PhD

Ming-Huang Chen, MD, PhD

Yi-Ping Hung, MD

San-Chi Chen, MD, PhD

Rheun-Chuan Lee, MD, PhD

Chun-Ying Wu, MD, PhD

Wei-Chen Lee, MD

Ming-Mon Hou, MD

Kun-Ming Chan, MD

Hong-Shiue Chou, MD

Ting-Jung Wu, MD, PhD

Tsung-Han Wu, MD

Po-Jung Su, MD

Chia-Hsun Hsieh, MD, PhD

Chan-Keng Yang, MD

Tsang-Wu Liu, MD, PhD

Objectives:

1. To evaluate the efficacy, in terms of tumor shrinkage, objective response rate, and down-stage rate, of nivolumab + ipilimumab as neoadjuvant therapy for patients with HCC;
2. To evaluate the safety profile in patients with HCC who receive neoadjuvant nivolumab + ipilimumab treatment;
3. To collect HCC tumor tissue and peripheral blood samples from the patients for a comprehensive biomarker evaluation for nivolumab + ipilimumab immunotherapy.

Immune checkpoint inhibitor therapy represents the major breakthrough of anticancer drug therapy development in recent years. Inhibitors targeting the cytotoxic T-lymphocyte antigen 4 (CTLA-4) or the programmed death-1 (PD-1) checkpoints have shown antitumor activity in multiple cancer types. Combination of anti-CTLA-4 and anti-PD-1 therapy may increase the objective response rate for patients with advanced cancers and thus may further improve the treatment efficacy. The anti-PD-1 drug nivolumab recently got approval by US FDA for the treatment of advanced hepatocellular carcinoma (HCC) patients who have been treated with sorafenib. Preliminary data also suggested that combination of nivolumab and anti-CTLA-4 therapy could increase the objective response rate for advanced HCC, with a better safety profile compared with conventional combination therapies (cytotoxic chemotherapy or molecular targeted therapy). This project aims to explore whether the high response rate produced by the combination of anti-PD-1 and anti-CTLA-4 may improve the treatment efficacy of HCC patients who are potentially eligible for curative surgery.

This is a single-arm, open-label trial. Eligible subjects must have histological diagnosis of HCC and fulfilling one of the following criteria of 'potentially eligible for curative surgery': (a) AJCC T3 tumor(s) (tumor with macrovascular invasion); (b) AJCC T2 tumors with multiple tumors and bilateral lobes involvement, none more than 5 cm; (c) AJCC T2 tumors with tumor number \> 3, none more than 5 cm; (d) AJCC T2 tumors with multiple tumors none more than 5 cm, with significant portal hypertension (splenomegaly, esophageal varices or platelet \< 100,000/μL); or (e) solitary tumor \> 5 cm, with significant portal hypertension (splenomegaly, esophageal varices or platelet \< 100,000/μL) ; (f) Other conditions that are considered high-risk for recurrence after surgery, e.g., direct diaphragmic invasion suspected by imaging。Eligible subjects must have ECOG performance status 0 or 1, Child-Pugh class A liver function, and measurable tumors (by RECIST 1.1). All enrolled subjects will receive nivolumab 3 mg/kg plus ipilimumab 1 mg/kg intravenously on day 1 of each cycle (every 3 weeks). Tumor assessment will be done after 6 weeks (2 cycles) and 12 weeks (4 cycles). Subjects who are considered eligible for curative surgery will receive surgery, while those considered not eligible for surgery will receive other anti-cancer therapy according to current practice guidelines (e.g., trans-catheter arterial chemoembolization). Samples will be collected from the subjects' tumor tissue, peripheral blood, and stool for studies of immune biomarkers.

The primary endpoint is the percentage of subjects with tumor shrinkage (\> 10% of decrease of the sum of the target lesions according to RECIST 1.1) after study drug treatment. It is estimated that about 30-50% subjects may have tumor shrinkage after 2-4 cycles of nivolumab + ipilimumab treatment. With type 1 error 0.05；power=0.9，P0=0.30, P1=0.55 respectively, 40 evaluable subjects (subjects who receive at least 2 cycles of study drug treatment and receive the first scheduled assessment of tumor response, assuming a 10% dropout rate) will be required. The study is expected to complete enrollment in 2 years.

Nivolumab Plus Ipilimumab as Neoadjuvant Therapy for Hepatocellular Carcinoma (HCC)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
BIOLUMA: Biomarkers for Nivolumab and Ipilimumab and Evaluation of the Combination in Lung Cancer	NCT03083691	Carcinoma, Non-... Carcinoma, Smal...	Nivolumab, Ipil... Nivolumab, Ipil...	18 Years -	Lung Cancer Group Cologne
Nivolumab Plus Ipilimumab as Neoadjuvant Therapy for Hepatocellular Carcinoma (HCC)	NCT03510871	Hepatocellular ...	nivolumab, ipil...	20 Years -	National Health Research Institutes, Taiwan

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