Subsequent Line Gemcitabine and Nivolumab in Treating Participants With Metastatic Small Cell Lung Cancer

• Sponsor: Wake Forest University Health Sciences (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03662074
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 14
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 44.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This phase II pilot trial studies how well gemcitabine and nivolumab work in treating participants with small cell lung cancer that has spread to other parts of the body after other treatments have failed. Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Giving second-line gemcitabine and nivolumab may work better in treating participants with small cell lung cancer.

Condition or Disease	Intervention/Treatment	Phase
Small Cell Lung Carcinoma; Stage IV Lung Cancer AJCC v8; Stage IVA Lung Cancer AJCC v8; Stage IVB Lung Cancer AJCC v8	Drug: Gemcitabine; Biological: Nivolumab	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To compare response rate (RR) of gemcitabine and nivolumab (G+N) after 4 cycles (8 weeks) to historical controls treated with nivolumab alone.

SECONDARY OBJECTIVES:

1. To compare median overall survival (OS) of G+N to historical controls treated with nivolumab alone.

2. To compare median progression-free survival (PFS) of G+N to historical controls treated with nivolumab alone.

3. To evaluate for tolerability of G+N at each treatment cycle and then every 8 weeks after treatment is completed.

EXPLORATORY OBJECTIVES:

1. To correlate immunophenotypic changes among lymphocytes (quantitative measurements of CD4 and CD8 T-cells) with radiographic response and overall survival before treatment, after treatment and between 8-12 weeks after treatment.

2. Among those patients with tumor mutation burden (TMB) status available, to describe the association between TMB (low, medium, or high) and RR, OS, and PFS.

3. Assess the patient perspective of symptomatic adverse events using self-reported items from the National Cancer Institute (NCI) Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE).

OUTLINE:

Participants receive gemcitabine intravenously (IV) over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 30 days, 6-10 weeks, and every 8 weeks thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Pilot Study of Subsequent Line Gemcitabine and Nivolumab for Advanced SCLC
• Actual Study Start Date: Nov 7, 2018
• Actual Primary Completion Date: Oct 7, 2020
• Anticipated Study Completion Date: Aug 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (gemcitabine, nivolumab) Participants receive gemcitabine IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity	Drug: Gemcitabine; Given IV; Other Names: dFdC dFdCyd Difluorodeoxycytidine ; Biological: Nivolumab; Given IV; Other Names: BMS-936558 MDX-1106 NIVO ONO-4538 Opdivo

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Positive Responses to Therapy Per Response Evaluation Criteria in Solid Tumors (RECIST) [Up to 8 weeks]

   Objective RR (complete response [CR] + partial response [PR]) will be compared between this study sample and a historical benchmark value of 10%. For this comparison we will use a one-sample test of proportion. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): Decrease by ≥ 30% in sum of longest diameter of target lesions. Stable Disease (SD): Not meeting criteria for CR, PR, or PD. Progressive Disease (PD): Increase by ≥ 20% in sum of longest diameter of target lesions or the appearance of one or more new lesions. The response in non-target lesions is defined as follows: Complete Response (CR): Complete disappearance of all non-target lesions. Stable Disease (SD): Persistence of one or more non-target lesion(s). Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Secondary Outcome Measures

1. Overall Survival (OS) - Number of Participants [Duration of time from the start of treatment to date of death, assessed up to 2 years]

   OS will be estimated using standard Kaplan Meier survival analysis methods.

2. Overall Survival (OS) - Months [Duration of time from the start of treatment to date of death, assessed up to 2 years]

   A median value (months) of overall survival will be estimated using standard Kaplan Meier survival analysis methods.

3. Progression-free Survival (PFS) - Number of Participants [Duration of time from the start of treatment to the time of investigator assessed progression or death, assessed up to 2 years]

   Progression-free survival will be estimated using standard Kaplan Meier survival analysis methods. Progression-Free Survival (PFS) is defined as the duration of time from the start of treatment to the time of investigator assessed progression or death. Progressive Disease (PD): Increase by ≥ 20% in sum of longest diameter of target lesions or the appearance of one or more new lesions

4. Progression-free Survival (PFS) - Months [Duration of time from the start of treatment to the time of investigator assessed progression or death, assessed up to 2 years]

   A median value (months) of progressive-free survival will be estimated using standard Kaplan Meier survival analysis methods. Progressive Disease (PD): Increase by ≥ 20% in sum of longest diameter of target lesions or the appearance of one or more new lesions

5. Number of Adverse Events [Up to 2 years]

   Toxicity rates will be estimated by responder status and presented overall and by body site per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed incurable SCLC and have had prior treatment with platinum-based chemotherapy. High-grade neuroendocrine tumors that are suspected to be of bronchopulmonary origin can be enrolled if they have had prior treatment with a SCLC chemotherapy regimen (e.g. platinum plus etoposide).

• Patients should not be demonstrating end-organ damage due to rapid progression of disease based on the most recent assessment of the treating physician.

• Patients must have radiographically measurable metastatic disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

• Absolute neutrophil count >= 1,500/mcL.

• Platelets >= 100,000/mcL.

• Chemotherapy agents are known to be teratogenic, therefore women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

• Ability to understand and the willingness to sign an Institutional Review Board (IRB)-approved informed consent document.

Exclusion Criteria:

• Patients who have previously received either gemcitabine or an immune checkpoint inhibitor can be enrolled.

• Emergent need for palliative radiation.

• Patients may not be receiving any other investigational agents for the treatment of nonsmall cell lung cancer.

• History of allergic reaction to gemcitabine.

• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects with chemotherapy. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with chemotherapy, breastfeeding should be discontinued.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157

Sponsors and Collaborators

• Wake Forest University Health Sciences
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Thomas W. Lycan, Wake Forest University Health Sciences

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 20, 2020
• Informed Consent Form - Jun 10, 2020

More Information

Publications

None provided.

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT03662074
• Other Study ID Numbers: IRB00051024; NCI-2018-01803; CCCWFU 62418; P30CA012197
• First Posted: Sep 7, 2018
• Last Update Posted: Nov 12, 2021
• Last Verified: Oct 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Lung Neoplasms; Small Cell Lung Carcinoma; Gemcitabine; Nivolumab

Study Results

Participant Flow

Arm/Group Title	Treatment (Gemcitabine, Nivolumab)
Arm/Group Description	Participants receive gemcitabine IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity Gemcitabine: Given IV Nivolumab: Given IV
Period Title: Overall Study
STARTED	14
COMPLETED	14
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Gemcitabine, Nivolumab)
Arm/Group Description	Participants receive gemcitabine IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity Gemcitabine: Given IV Nivolumab: Given IV
Overall Participants	14
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.8 (8.9)
Sex: Female, Male (Count of Participants)
Female	5 35.7%
Male	9 64.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	14 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 14.3%
White	12 85.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	14 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Positive Responses to Therapy Per Response Evaluation Criteria in Solid Tumors (RECIST)
Description	Objective RR (complete response [CR] + partial response [PR]) will be compared between this study sample and a historical benchmark value of 10%. For this comparison we will use a one-sample test of proportion. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): Decrease by ≥ 30% in sum of longest diameter of target lesions. Stable Disease (SD): Not meeting criteria for CR, PR, or PD. Progressive Disease (PD): Increase by ≥ 20% in sum of longest diameter of target lesions or the appearance of one or more new lesions. The response in non-target lesions is defined as follows: Complete Response (CR): Complete disappearance of all non-target lesions. Stable Disease (SD): Persistence of one or more non-target lesion(s). Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Time Frame	Up to 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Gemcitabine, Nivolumab)
Arm/Group Description	Participants receive gemcitabine IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity Gemcitabine: Given IV Nivolumab: Given IV
Measure Participants	14
Partial response	1 7.1%
Progressive disease	11 78.6%
Lost to follow up	2 14.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment (Gemcitabine, Nivolumab)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		The pre-specified analysis plan as per the protocol is to proceed to the second stage of recruitment for additional participants if the response proportion exceeds the historical control of 10%.

2. Secondary Outcome

Title	Overall Survival (OS) - Number of Participants
Description	OS will be estimated using standard Kaplan Meier survival analysis methods.
Time Frame	Duration of time from the start of treatment to date of death, assessed up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Gemcitabine, Nivolumab)
Arm/Group Description	Participants receive gemcitabine IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity Gemcitabine: Given IV Nivolumab: Given IV
Measure Participants	14
Deaths - any reason	8 57.1%
Survivors	6 42.9%

3. Secondary Outcome

Title	Overall Survival (OS) - Months
Description	A median value (months) of overall survival will be estimated using standard Kaplan Meier survival analysis methods.
Time Frame	Duration of time from the start of treatment to date of death, assessed up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Gemcitabine, Nivolumab)
Arm/Group Description	Participants receive gemcitabine IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity Gemcitabine: Given IV Nivolumab: Given IV
Measure Participants	14
Median (95% Confidence Interval) [months]	3.2

4. Secondary Outcome

Title	Progression-free Survival (PFS) - Number of Participants
Description	Progression-free survival will be estimated using standard Kaplan Meier survival analysis methods. Progression-Free Survival (PFS) is defined as the duration of time from the start of treatment to the time of investigator assessed progression or death. Progressive Disease (PD): Increase by ≥ 20% in sum of longest diameter of target lesions or the appearance of one or more new lesions
Time Frame	Duration of time from the start of treatment to the time of investigator assessed progression or death, assessed up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Gemcitabine, Nivolumab)
Arm/Group Description	Participants receive gemcitabine IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity Gemcitabine: Given IV Nivolumab: Given IV
Measure Participants	14
Participants that had disease progression	11 78.6%
Participants that did not have disease progression	3 21.4%

5. Secondary Outcome

Title	Progression-free Survival (PFS) - Months
Description	A median value (months) of progressive-free survival will be estimated using standard Kaplan Meier survival analysis methods. Progressive Disease (PD): Increase by ≥ 20% in sum of longest diameter of target lesions or the appearance of one or more new lesions
Time Frame	Duration of time from the start of treatment to the time of investigator assessed progression or death, assessed up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Gemcitabine, Nivolumab)
Arm/Group Description	Participants receive gemcitabine IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity Gemcitabine: Given IV Nivolumab: Given IV
Measure Participants	14
Median (95% Confidence Interval) [months]	1.8

6. Secondary Outcome

Title	Number of Adverse Events
Description	Toxicity rates will be estimated by responder status and presented overall and by body site per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Gemcitabine, Nivolumab)
Arm/Group Description	Participants receive gemcitabine IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity Gemcitabine: Given IV Nivolumab: Given IV
Measure Participants	14
Number [Number of adverse events reported]	12

Adverse Events

Time Frame	2 years
Arm/Group Title	Treatment (Gemcitabine, Nivolumab)
Arm/Group Description	Participants receive gemcitabine IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity Gemcitabine: Given IV Nivolumab: Given IV
All Cause Mortality
	Treatment (Gemcitabine, Nivolumab)
	Affected / at Risk (%)	# Events
Total	8/14 (57.1%)
Serious Adverse Events
	Treatment (Gemcitabine, Nivolumab)
	Affected / at Risk (%)	# Events
Total	1/14 (7.1%)
Metabolism and nutrition disorders
Hyponatremia	1/14 (7.1%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Gemcitabine, Nivolumab)
	Affected / at Risk (%)	# Events
Total	11/14 (78.6%)
Gastrointestinal disorders
Diarrhea	1/14 (7.1%)	1
Fecal incontinence	1/14 (7.1%)	1
Gastrointestinal pain	1/14 (7.1%)	1
Nausea	1/14 (7.1%)	1
Vomiting	1/14 (7.1%)	1
General disorders
Fatigue	1/14 (7.1%)	1
Fever	1/14 (7.1%)	1
Infections and infestations
Lung infection	2/14 (14.3%)	2
Nervous system disorders
Syncope	1/14 (7.1%)	1
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage	1/14 (7.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.