Depletion of Myeloid Derived Suppressor Cells to Enhance Anti PD-1 Therapy

NCT03302247 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: TH-113
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

Metastatic non small cell lung cancer can be treated with cytotoxic chemotherapy or using recently approved immunotherapy with antibody, Nivolumab. Both the therapies have limitation due to development of tolerance or immunosuppression. This trial combines one drug from each category, immunotherapeutic Nivolumab and chemotherapeutic gemcitabine as it was reported that gemcitabine reduces immunosuppression by killing myeloid derived suppressor cells, thereby increasing the efficacy of Nivolumab.

Conditions

Non Small Cell Lung Cancer Stage IIIB

Outcome Measures

Primary Outcomes (1)

• Decrease in Macrophage Derived Suppressor Cells (MDSC) Numbers as a Result of Treatment With Gemcitabine.

  Immunosuppression in terms of number of circulating MDSC in the blood by comparing within each arm reduction in the number of MDSCs after each cycle of treatment

  2 years

Secondary Outcomes (1)

• Increase in T-cell Activity

  2 years

Study Arms (1)

Nivolumab+Gemcitabine

EXPERIMENTAL

Nivolumab infusion on day 1 and 15 with the addition of gencitabine on day 1, 8 and 15 of 28 day cycle

Biological: Nivolumab; Drug: Nivolumab+Gemcitabine

Interventions

Nivolumab BIOLOGICAL

Monoclonal antibody against non small cell lung cancer

Nivolumab+Gemcitabine

Nivolumab+Gemcitabine DRUG

Gemcitabine is added to the Nivolumab treatment

Nivolumab+Gemcitabine

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed diagnosis of non-small cell lung cancer (NSCLC). Patients should have stage IV disease (AJCC 7th edition), stage IIIb disease that is not amenable to potentially curative treatment (e.g. chemoradiotherapy) or unequivocal progression in a prior irradiated field. Measurable or evaluable disease is required.
• Fresh/ archived tumor tissue available for molecular marker testing is required for entry. A tumor block or at least 5 unstained slides must be available. As an alternative FFPE cell block that is sufficient for histologic analysis is acceptable. If a patient has had PD-L1 status previously determined with and FDA approved assay, they have met this requirement. Tissue is still requested (but not required) for further analysis
• Age \> 18 years.
• ECOG performance status 0 or 1
• Patients must have normal organ and marrow functions as defined below:
• White blood cells (WBC) \>2,000/mcL; Platelets \>100,000/mcL; Hb ≥9g/dl; Absolute neutrophil count (ANC) \>1,500/mcL; Serum creatinine ≤1.5 x ULN, or
• Creatinine clearance (CrCl) ≥50 ml/min (if using Cockcroft Gault formula below):
• Female CrCl= ((140 - age in years)/(72 x serum creatinine in mg/dL)) x weight in kg x 0.85; Male CrCl= ((140 - age in years)/(72 x serum creatinine in mg/dL) x weight in kg x 1.0; AST/SGOT ≤ 3 x ULN
• Total bilirubin:
• If no known liver metastasis: total bilirubin ≤ 1.5 x institutional upper limit (ULN) (except, subjects with Gilbert Syndrome who may have total bilirubin \< 3.0 mg/dl; If known metastasis: total bilirubin ≤ 5 ULN
• Negative serum pregnancy test result in Women os Child -bearing Potential (WOCBP)
• Prior therapies:
• Patients without activating mutations and gene rearrangements should have received at least one prior chemotherapy regimen. Any number of prior therapies is allowed except for immunotherapy (e.g. anti PD-1, PD-L1, vaccines, CTLA-4 etc.),
• Patients with activating mutations with known documented benefit from tyrosine kinase inhibitors should have received and demonstrated progression with that inhibitor (e.g. EGFR del 19 mutation should have been treated with gefitinib, erlotinib or afatanib etc). ALK rearrangements should have been treated with an ALK inhibitor. Patients who have progressed on these agents should be assessed, if appropriate, for resistance mutations susceptible to approved agents and treated with that agent.
• No prior gemcitabine treatment

You may not qualify if:

• Patients with active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
• Patients requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if \> 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
• As there is a potential for hepatic toxicity with nivolumab, drugs with predisposition to hepatotoxicity should be used with caution in patients treated with nivolumab-containing regimen.
• Patients are excluded if they have active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if metastases have been treated without clinical or radiologic evidence of progression for 14 days prior to initiation of treatment. An MRI within 14 days of commencing therapy is required for patients with a history of brain metastases.
• There must be no requirement for immunosuppressive doses of systemic corticosteroids (\>10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab.
• Uncontrolled inter-current illness that would increase the risk of toxicity or limit compliance with study requirements. This includes but is not limited to, uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness or social situations that would limit compliance with study requirements.
• Known HIV-positive patients on combination antiretroviral therapy are ineligible because of the abnormal immune response that results from HIV disease.
• Patients should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
• Patients who have had systemic (IV) cytotoxic chemotherapy or any other investigational agents within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. If a patient received an oral agent, treatment on study can not commence at least five half-lives of the agent have elapsed.
• Subjects with previous malignancies (except non-melanoma skin cancers, and in situ cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period.
• Other active malignancy requiring concurrent intervention.
• Subjects with any history of interstitial lung disease.
• Pregnant or breast feeding.

Sponsors & Collaborators

• Fox Chase Cancer Center: lead

Study Sites (1)

Fox Chase Cancer Center - Philadelphia

Philadelphia, Pennsylvania, 19111-2497, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Nivolumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Martin Edelman
• Organization: Fox Chase Cancer Center

Martin.Edelman@fccc.edu

215-728-5682

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Nivolumab 240mg, IV on day 1, 15 + Gemcitabine 1000mg/m2, IV on day 1, 8, 15 of 28 days cycle

Study Record Dates

• First Submitted: September 27, 2017
• First Posted: October 5, 2017
• Study Start: January 15, 2018
• Primary Completion: March 21, 2019
• Study Completion: July 12, 2019
• Last Updated: October 28, 2020
• Results First Posted: October 28, 2020

Record last verified: 2020-10

Locations

US (1)