Marrow Infiltrating Lymphocytes - Non-Small Cell Lung Cancer (MILs™ - NSCLC) Alone or in Combination With Nivolumab With or Without Tadalafil in Locally Advanced and Unresectable or Metastatic NSCLC

Lung Cancer Clinical Trial

Official title:

A Phase 2a, Open-Label, Multi-Center Study to Assess the Efficacy and Safety of Marrow Infiltrating Lymphocytes - Non-Small Cell Lung Cancer (MILs™ - NSCLC) Alone or in Combination With Nivolumab With or Without Tadalafil in Subjects With Locally Advanced and Unresectable or Metastatic NSCLC Previously Treated With Anti-PD-1

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04069936
• Other study ID #: CLN-P18001
• Status: Terminated
• Phase: Phase 2
• Start date: October 15, 2019
• Est. completion date: November 30, 2021

Study information

• Verified date: July 2022
• Source: WindMIL Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the safety and efficacy of MILs™ - NSCLC alone and in combination with nivolumab with or without tadalafil in subjects with locally advanced and unresectable or metastatic NSCLC who are refractory or relapsing to a PD-1 containing regimen.

Description:

This study will examine the safety and efficacy of Marrow Infiltrating Lymphocytes-Non-Small Cell Lung Cancer (MILs™ - NSCLC) combined with nivolumab with or without tadalafil in subjects with locally advanced and unresectable and metastatic NSCLC who were refractory to, or have relapsed on, an anti-PD-1 containing regimen. MILs™ - NSCLC are an adoptive cell therapy product derived via the activation and expansion of bone marrow T cells. Subjects will have bone marrow harvested during the Screening Period which will be used to manufacture the MILs™ - NSCLC. The MILs™ - NSCLC will then be administered on Day 0. Nivolumab will be administered on Day 1 and will continue every four weeks until treatment discontinuation. Tadalafil will be administered on Day 1 and will continue daily until treatment discontinuation.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 19
• Est. completion date: November 30, 2021
• Est. primary completion date: October 28, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.

2. Locally advanced and unresectable, or metastatic NSCLC.

3. Histologically or cytologically confirmed, either squamous or non-squamous NSCLC.

4. Measurable disease as per RECIST 1.1

5. Willingness to undergo bone marrow aspiration (BMA).

6. No more than one treatment regimen following an anti-PD-1 antibody containing treatment regimen prior to BMA collection.

a. Subjects may have BMA collected while on an anti-PD-1 antibody containing treatment regimen or while on a treatment regimen immediately following an anti-PD-1 antibody containing treatment regimen.

7. BMA may be collected while on an anti-PD-1 antibody containing treatment regimen or while on a treatment regimen immediately following an anti-PD-1 antibody containing treatment regimen. However, the subjects must have radiographic evidence of disease progression prior to lymphodepletion.

8. = 21 days have lapsed since last cytotoxic chemotherapy treatment prior to collection of the BMA.

9. Previous treatment with the appropriate targeted therapy if the subject has known EGFR/ALK/ROS1 rearrangements.

10. Willingness to provide a fresh tumor biopsy during Screening Period or formalin-fixed, paraffin-embedded tissue collected at the time of most recent relapse. Note: Archival tissue regardless of biopsy date may be considered.

11. Adequate renal, hepatic and bone marrow function defined as total bilirubin </= 1.5 x ULN (except for subjects with Gilbert's disease = 3.0 x ULN with direct bilirubin </= 1.5 x ULN ). Aminotransferase (AST) / Alanine Aminotransferase (ALT) </= 3.0 X ULN (subjects with liver involvement will be allowed </= 5.0 X ULN). Serum creatinine </= 1.5 x ULN; if serum creatinine is 1.5 to 2.0 × ULN, then the creatinine clearance (calculated using the Cockcroft-Gault formula or measured) must be = 40 mL/min. Lymphocyte >/= 0.7 x 10^9/L. ANC >/= 1.5 x 10^9/L. Platelets >/= 100 × 10^9/L. WBC >/= 2.0 ×10^9/L. Hemoglobin > 9.0 g/dL.

12. Women of childbearing potential and male subjects (even if they are surgically sterilized or had a vasectomy) and their partners must agree to abstain or to use an effective form of birth control during the study for at least 6 months following administration of the last dose of lymphodepletion or for at least 5 months following the last dose of nivolumab for females and 7 months for males, whichever is longer. In addition, male subjects must not donate sperm during this period.

13. Capable of giving and has provided a signed ICF, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria:

1. Insufficient activation/expansion of T cells or other problems with the subject's MILs™ - NSCLC product which would prohibit administration.

2. Major surgical procedure within 7 days of the first dose of lymphodepletion treatment.

3. Prior malignancy active within the previous 3 years from date of BMA collection except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.

4. Subjects with symptomatic uncontrolled brain metastases requiring treatment with steroids or anti-seizure medications within 28 days prior to the BMA are excluded. However, participants with brain metastases that have been previously treated and are stable on subsequent scan(s) are allowed and subjects with untreated possible brain metastases that are new at the time of screening and are < 1 cm and asymptomatic are allowed. Subjects with asymptomatic untreated CNS disease may undergo BMA prior to treatment of such disease.

5. Infection requiring treatment with intravenous antibiotics, antifungal, or antiviral agents within 7 days prior to the BMA.

6. Presence of an autoimmune disease requiring active systemic treatment.

7. Clinically significant, uncontrolled cardiovascular disease, including congestive heart failure Grade III or IV according to the New York Heart Association classification, myocardial infarction or unstable angina within the previous 6 months prior to BMA collection.

8. Known diagnosis of human immunodeficiency virus (HIV) or active viral hepatitis.

9. Administration of neutrophil growth factor support within 14 days prior to the BMA.

10. Use of systemic corticosteroids (glucocorticoids) for greater than one day within 28 days prior to the BMA.

11. Planned use of systemic corticosteroids (glucocorticoids) for greater than one day within 28 days prior to MILs™ - NSCLC administration.

12. Prior radiation to both sides of the pelvis. Prior radiation to one side of the pelvis is permitted as long as the other side of the pelvis.

13. Subjects with history of life-threatening toxicity related to prior immune therapy except those that are unlikely to re-occur with standard countermeasures.

14. Receipt of live attenuated vaccine within 30 days of planned Day 0.

15. History of allergy or hypersensitivity to MILs™-NSCLC, cyclophosphamide, fludarabine, nivolumab, tadalafil or their components.

16. Pregnant or lactating females.

17. Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator's opinion, could affect the safety of the subject or impair the assessment of study results.

18. Unwilling or unable to comply with the protocol.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Cancer
• Lung Cancer Metastatic
• Lung Cancer, Non-small Cell
• Lung Neoplasms
• Neoplasms
• Non Small Cell Lung Cancer
• Non Small Cell Lung Cancer Metastatic
• Non-small Cell Lung Cancer
• Non-small Cell Lung Cancer Metastatic
• NSCLC

Intervention

Biological:
• MILs™ - NSCLC
To evaluate the safety of MILs™ - NSCLC alone in subjects with locally advanced and unresectable or metastatic NSCLC
• nivolumab
To evaluate the efficacy of MILs™ - NSCLC in combination with nivolumab in subjects with locally advanced and unresectable or metastatic NSCLC

Drug:
• tadalafil
To evaluate the efficacy of MILs™ - NSCLC in combination with nivolumab with or without tadalafil in subjects with locally advanced and unresectable or metastatic NSCLC

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	Cleveland Clinic	Cleveland	Ohio
United States	Karmanos Cancer Center	Detroit	Michigan
United States	City of Hope	Duarte	California
United States	University of California - Los Angeles	Los Angeles	California
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Washington University	Saint Louis	Missouri
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
WindMIL Therapeutics	Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse Events per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 5.0	Incidence, intensity, and type of AE	From ICF through 100 days after the last dose of study treatment
Primary	Serious Adverse Events per NCI-CTCAE version 5.0	Incidence, intensity, and type of SAE	From ICF through 100 days after the last dose of study treatment
Primary	Overall Response Rate (ORR) of MILs™ - NSCLC in combination with nivolumab with or without tadalafil	Proportion of subjects with reduction in tumor burden of a predefined amount per RECIST 1.1	24 months
Secondary	Duration of response	Duration from first documented evidence of CR or PR until the first documented evidence of PD or death due to any cause, whichever occurs first	up to 5 years after treatment discontinuation
Secondary	Disease control rate	Proportion of subjects in the efficacy population who achieve an Investigator-assessed confirmed CR, PR, or SD per RECIST 1.1	up to 5 years after treatment discontinuation
Secondary	Progression-free survival	Date of first the administration of MILs™ - NSCLC until documented PD or death due to any cause, whichever occurs first	up to 5 years after treatment discontinuation
Secondary	Overall survival	Duration from the date of administration of MILs™ - NSCLC until death due to any cause	up to 5 years after treatment discontinuation
Secondary	Overall Response Rate (ORR) of MILs™ - NSCLC	Proportion of subjects with reduction in tumor burden of a predefined amount per RECIST 1.1	24 months
Secondary	Safety of MILs™ - NSCLC alone and in combination with nivolumab with or without tadalafil as assessed by vital signs (pulse rate)	Pulse rate in beats/minute	From ICF through 100 days after the last dose of study treatment
Secondary	Safety of MILs™ - NSCLC alone and in combination with nivolumab with or without tadalafil as assessed by vital signs (weight)	Weight in pounds	From ICF through 100 days after the last dose of study treatment
Secondary	Safety of MILs™ - NSCLC alone and in combination with nivolumab with or without tadalafil as assessed by vital signs (blood pressure)	Systolic and diastolic blood pressure in mmHg	From ICF through 100 days after the last dose of study treatment
Secondary	Safety of MILs™ - NSCLC alone and in combination with nivolumab with or without tadalafil as assessed by vital signs (respiratory rate)	Respiratory rate in breaths/minute	From ICF through 100 days after the last dose of study treatment
Secondary	Safety of MILs™ - NSCLC alone and in combination with nivolumab with or without tadalafil as assessed by vital signs (temperature)	Termperature in Fahrenheit	From ICF through 100 days after the last dose of study treatment
Secondary	Safety of MILs™ - NSCLC alone and in combination with nivo. with or w/o tadalafil by liver function (ALT/AST (U/L), albumin (g/dL), tot. bilirubin (mg/dL)), kidney function (creatinine (mg/dL) and endocrine function (T3 free and T4 free (ng/dL))	Clinical chemistry results will be summarized and changes from baseline provided	From ICF through 100 days after the last dose of study treatment
Secondary	Safety of MILs™ - NSCLC alone and in combination with nivolumab with or without tadalafil by cell count (e.g. RBC (10^6/uL), WBC (10^3/uL), absolute cell count (10^3/uL), Hct (%) and Hgb (g/dL)	Hematology results will be summarized and changes from baseline provided	From ICF through 100 days after the last dose of study treatment
Secondary	Safety of MILs™ - NSCLC alone and in combination with nivolumab with or without tadalafil as assessed by APTT (seconds), fibrinogen (mg/dL), INR and protime (seconds)	Coagulation results will be summarized in data listings	From ICF through 100 days after the last dose of study treatment
Secondary	Safety of MILs™ - NSCLC alone and in combination with nivolumab with or without tadalafil as assessed by urine appearance, color, pH, specific gravity and presence of blood, bilirubin, glucose, ketone, leukocyte esterase, nitrite, protein, urobilinogen	Urinalysis results will be summarized in data listings	From ICF through 100 days after the last dose of study treatment
Secondary	Safety of MILs™ - NSCLC alone and in combination with nivolumab with or without tadalafil by electrocardiograms (ECGs) assessed by Investigators as normal, abnormal clinically significant or abnormal not clinically significant	ECGs results will be summarized and changes from baseline provided	From ICF through 100 days after the last dose of study treatment
Secondary	Safety of MILs™ - NSCLC alone and in combination with nivolumab with or without tadalafil by physical examination with abnormalities reported as adverse events	Physical examinations will be performed by the Investigators and any new clinically significant or changes in medical conditions will be reported as adverse events	From ICF through 100 days after the last dose of study treatment