Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Hypoglycemic Agents

All Drugs and Chemicals

Metformin

14 to 21 days of pre-operative Metformin tablets First 5 days 850 mg OD v/o 850 mg BID thereafter until 21 days are completed.

850 mg tablets v/o OD for first 5 days 850 mg tablets v/o BID until day 21

Tom Waddell, MD

This is a phase II single centre open label single arm pre-operative window of metformin treatment in stage I-IIIa Non small cell lung cancer.

In which patients will be invited to participate by receiving Metformin treatment during 14 to 21 days at 850 mg BID until the day before surgery.

They will be followed closely for any Adverse Events during treatment and 30 days after surgery. During treatment there will be no follow up tests except 1 fasting blood glucose at week 2 of treatment.

Survival data will be prospectively gathered after study treatment has ended until death.

Title of study: Phase II study of single agent pre-operative metformin in patients with clinical stage I - IIIA NSCLC proceeding to surgical resection. 'Lung Metcore Study'

Objectives:

To evaluate the effects of short-term pre-operative exposure to metformin in operable stages I to IIIA NSCLC.

Primary end-points:

* The difference in the proportion of proliferating NSCLC cells (measured by comparing Ki67 levels) prior to and after metformin treatment.
* The rate of apoptosis of NSCLC (measured by the TUNEL assay) prior to and after metformin treatment.

Secondary end-points:

* The safety and tolerability of preoperative metformin administration in NSCLC, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE \[version 4.0\])
* Pathologic changes in lung tissue after metformin administration. Study Design: This trial is designed as a single center, open label, single arm Phase II study of a pre-operative window of metformin treatment in stages I - IIIA NSCLC. The efficacy of metformin will be assessed by its effects on markers of cellular proliferation and apoptosis. Exploratory analysis of molecular markers of the hypothesized effects of metformin in NSCLC will also be carried out. Furthermore, changes in serum ligands to growth signaling pathways in lung cancer with metformin treatment will be measured.

Number of patients: Thus, the total expected sample size is approximately 50 patients, anticipating minimal loss of eligible participants through treatment intolerance or acceleration of surgery. Accrual is estimated at 1.5 to 2 patients per month for 25 to 33 months, based on accrual rates for a recent pre-operative window thoracic surgical study at UHN.

• Metformin will be started at a dose of 850mg daily then increased to 850mg b.i.d. (morning and evening) after 5 days as tolerated. Treatment will be given from the time of enrollment till the evening prior to surgery.

Correlatives:

The following molecular and serological correlative biomarkers will be considered covariates in the analysis of primary endpoints of the phase II study. Covariate pretreatment values and changes in covariate values (where applicable) will be used to estimate the relationship between covariates and patient's Ki67 or apoptotic response using logistic regression. It is noted that several covariates are being tested and the number of patients being analyzed is small, thus, some tests may be statistically significant due to chance even if no association exists.

* Genetic Mutations in NSCLC (On pre-treatment biopsies by molecular techniques):

  * LKB1 mutational status (Sequencing)
  * EGFR, Ras, AKT, PI3K mutations (Oncocarta platform)
  * EGFR gene copy number (FISH)
  * ALK rearrangement status
* Protein Marker of Resistance To Metformin (On pre-treatment biopsies by immunohistochemistry

  * OCT1 expression
  * PROTEIN MARKERS OF RECEPTORS AND ACTIVATED PATHWAYS TO mtor IN NSCLC (Comparison between pre-treatment biopsies and post-resection specimens by immunohistochemistry):
  * IR
  * IGF-1R
  * Phosphorylated-AMPK
  * EGFR and phospho-EGFR
  * PKB (AKT) and phospho-AKT
  * Phosphorylated (erbb2, erbb3, erbb4)
  * Phosphorylated-STAT3
  * Phospho-ribosomal protein S6
* VASCULARITY IN NSCLC (Comparison between pre-treatment biopsies and post-resection specimens by immunohistochemistry):

  * VEGF
  * Microvessel density count (CD34, CD105)
* SERUM LIGANDS TO SIGNALLING PATHWAYS IN NSCLC (Comparison between pre-treatment biopsies and post-resection specimens by ELISA):

  * Insulin
  * Glucose
  * IGF-1
  * TGF-α
  * TNF-α
  * Calculated HOMA
  * CRP
  * Adiponectin

Statistics:

Patients who completed metformin treatment will have the Ki67 and apoptosis scores compared between samples obtained pre and post-metformin treatment. Changes in Ki67 and apoptotic scores with metformin treatment will be correlated with the biomarkers of various pathways hypothesized to mediate an effect of metformin on NSCLC development.

single center, open label, single arm Phase II study of a pre-operative window of metformin treatment in stages I - IIIA NSCLC

Phase II Lung Metcore - Preoperative Metformin for Lung Cancer

Phase II Study of Single Agent Pre-operative Metformin in Patients With Clinical Stage I - IIIA NSCLC Proceeding to Surgical Resection. 'Lung Metcore Study'

• The difference in the proportion of proliferating NSCLC cells (measured by comparing Ki67 levels) prior to and after metformin treatment.

• The rate of apoptosis of NSCLC (measured by the TUNEL assay) prior to and after metformin treatment.

• The safety and tolerability of preoperative metformin administration in NSCLC, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE \[version 4.0\])

• Pathologic changes in lung tissue after metformin administration

University Health Network, Toronto

Infections

Symptoms and General Pathology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma, Squamous Cell

Communicable Diseases

Head and Neck Neoplasms

Papillomavirus Infections

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Sexually Transmitted Diseases

Sexually Transmitted Diseases, Viral

Virus Diseases

DNA Virus Infections

Tumor Virus Infections

Genital Diseases

Urogenital Diseases

Disease Attributes

Camurati-Engelmann Disease

Vaccines

Immunomodulating Agents

M7824 + TriAd vaccine (ETBX-011, ETBX-051 and ETBX-061) (Days 1)

M7824 + TriAd vaccine (Day 1) + N-803 (Day 1)

M7824 (1200 mg) will be administered intravenously on day 1 and 15 to patients enrolled in arm 1-3 (all three arms).

M7824

N-803 (15 mcg/kg, subcutaneously) will be given on day 1 to patients enrolled in arm 3.

N803

TriAd vaccine (5 x 10e(11) viral particles (VP); subcutaneous injection) will be given on day 1 to patients enrolled in arm 2 and arm 3

TriAd vaccine

Jason M Redman, M.D.

Background:

Some people who get head and neck cancer will need surgery to treat their cancer. Research suggests that immunotherapy drugs may help fight head and neck cancer if given before surgery. In most cases, there is enough time between cancer diagnosis and surgery to test immunotherapy drugs. In this study, researchers are testing the safety and anti-cancer abilities of 3 drugs given before surgery for head and neck cancer.

Objective:

To learn if giving M7824 alone, or with the TriAd Vaccine (ETBX-011, ETBX-051 \& ETBX-061), or with TriAd vaccine plus Anktiva (N-803) can shrink previously untreated head and neck tumors before surgery or stop the tumors from coming back after all treatment.

Eligibility:

People age 18 and older who have a head and neck cancer that has not been treated before, and the tumor must be removed with surgery.

Design:

Participants will be screened in a separate protocol.

Participants will have the following tests:

* medical history and physical exams
* computed tomography or magnetic resonance imaging scans
* tumor, mucosa, and skin biopsies
* electrocardiograms to monitor heart activity
* endoscopies (a tube is inserted through the nose to see the upper airway)
* blood and urine tests.

All participants will get bintrafusp alfa (M7824) through an intravenous infusion. For this, a small plastic tube is put into an arm vein. Some may also get the TriAd vaccine. It is injected under the skin on the arms or legs. Some may also get N-803. It is injected under the skin on the stomach.

Participants will have clinic visits while they are getting treatment and after treatment ends.

After treatment ends, participants will have their scheduled surgery. There will be two follow up visits at the National Institutes of Health (NIH) after your surgery. They will be contacted by phone or email every 2 weeks for 3 months. Then they will be contacted every 3 months for 2 years.

...

Background:

* Approximately 50% of patients with advanced, non-human papilloma virus (HPV) associated head and neck squamous cell carcinoma (HNSCC) will develop locoregional or distant relapse within two years of completing definitive standard-of-care treatment.
* Two ongoing clinical trials investigating neoadjuvant programmed cell death protein 1 (PD-1) blockade before surgical resection of HNSCC suggest that immunotherapy can both cytoreduce existing disease before surgery and reduce the risk of locoregional or distant disease relapse after surgery.
* Preliminary data from these studies suggest neoadjuvant treatments can be administered without delaying planned surgical intervention.
* Experiments conducted by the Laboratory of Tumor Immunology and Biology (LTIB) demonstrated synergistic activity with tumor-targeted adenoviral vaccine plus bintrafusp alfa (M7824) plus Anktiva (N-803) in humanized mice bearing human carcinomas and in vitro studies.
* M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand 1(PD-L1) antibody and the extracellular domain of transforming growth factor beta (TGF-beta) receptor type 2, a TGF-beta trap.
* Adenoviral vaccines targeting known shared tumor antigens can generate antigen-specific T cells.
* N-803 is an interleukin 15 (IL-15)/interleukin 15 receptor (IL-15R) alpha super agonist complex that can enhance both natural killer (NK) cell and T cell anti-tumor activity via expansion and activation.
* Activity observed with neoadjuvant anti-PD-1 agents alone provides rationale for testing of M7824 alone and in combination with other immune-oncologic agents that have been shown to work in concert with M7824 in preclinical studies.
* Analysis of pre- and post-treatment tissues from HNSCC patients presents a unique opportunity to interrogate the effects the above treatment(s) on tumor.
* A dose escalation of N-803 in combination with a flat dose of M7824 was conducted at the National Cancer Institute. Thirteen patients have been treated with the combination. No dose limiting toxicities (DLTs) were observed.

Objectives:

-Determine the rate of pathologic complete response (pCR) or clinical-to-pathological downstaging in patients with previously untreated intermediate/high risk, non-HPV associated, squamous cell carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, III or IV) who receive any of the three proposed treatments: M7824 alone, M7824 plus TriAd vaccine, or M7824 plus TriAd vaccine plus N803 prior to definite surgery.

Eligibility:

* Patients must have histologically or cytologically confirmed, previously untreated intermediate/high risk, p16-negative (if oropharyngeal), squamous cell carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, III or IV)
* Men or Women; Age greater than or equal to 18 years
* Eastern Cooperative Oncology Office (ECOG) performance status less than or equal to 1

Design:

* This protocol is a sequential window of opportunity trial of Anti-PD-L1/TGF-beta trap (M7824) alone and in combination with TriAd Vaccine (ETBX-011, ETBX-051 \& ETBX-061) and N-803 for non-HPV associated resectable Head and Neck Squamous Cell Carcinoma (HNSCC).
* Patients will be referred to the National Institutes of Health (NIH) for this immunotherapy treatment from surrounding academic medical centers and private physicians.
* Upon referral to the NIH, patients will be rapidly screened, and enrolled on the protocol, if appropriate.
* This trial will enroll patients in three arms sequentially to permit safety evaluation before adding the next agent.
* In the first arm of 12 patients, M7824 (1200 mg) will be administered intravenously on day 1 and 15.
* If no safety concerns, accrual will proceed to the 2nd arm, and 12 patients will enroll with M7824 (1200mg; intravenous) treatment on day 1 and 15 and TriAd vaccine (5 x 10 (11) viral particles (VP; subcutaneous) treatment on day 1 only.
* If no safety concerns, accrual will proceed to the 3rd arm, and 12 patients will enroll with M7824 ((1200mg; intravenous) treatment on day 1 and 15 plus TriAd vaccine (5 x 10(11) VP; subcutaneous injection) and N-803 (15mcg/kg, subcutaneously) treatment on day 1.
* After obtaining pre-treatment biopsies, imaging and blood collection, patients will receive the neoadjuvant immunotherapy at the NIH Clinical Center.
* Patients will then be sent back to their referring providers for their definitive standard of care surgery and adjuvant therapy as indicated based upon pathologic analysis of the surgical specimen. National Cancer Institute (NCI) investigators will have no role in directing the ensuing standard of care surgeries performed at outside institutions.
* For consistency in pathologic analysis of resection specimens, tissue blocks and/or slides will be obtained from outside institutions and be reviewed by the NCI Laboratory of Pathology.
* It is expected that up to 20 patients may enroll in one year. Thus, with 3 arms of 12 patients apiece, up to 36 evaluable patients may enroll. Accrual is expected to be completed within 2 years.

Anti-PD-L1/TGF-beta Trap (M7824) Alone and in Combination With TriAd Vaccine and N-803 for Resectable Head and Neck Squamous Cell Carcinoma Not Associated With Human Papillomavirus Infection

A Sequential Window of Opportunity Trial of Anti-PD-L1/TGF-beta Trap (M7824 ) Alone and in Combination With TriAd Vaccine, and N-803 for Resectable Head and Neck Squamous Cell Carcinoma Not Associated With Human Papillomavirus Infection.

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. All large- scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Resected tumors were reviewed one month after being on study to determine a pCR, defined as absence of malignant cells in the resected tumor specimen. A pathologist examines tumor specimens to look for malignant cells.

Clinical-to-pathologic downstaging is when the numerical pathological stage is lower than the initial numerical clinical stage (i.e., II to I)

Response was measured by CT imaging and the RECIST to determine whose tumors shrunk after therapy. CR is disappearance of all target lesions, and PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 3 is severe. Grade 4 is life-threatening. Permanent treatment discontinuation is required in some cases of immune-related Grade 4 AEs (e.g., Grade 4 rash/inflammatory dermatitis, nephritis,..). Permanent treatment discontinuation is not required when the AE is manifested by a single laboratory value out of normal range without any clinical correlates.

Probability of being alive and recurrence (disease) free after treatment reported along with 95% confidence intervals. Response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Disease recurrence is defined as the cancer comes back evidenced by imaging, clinical exam and/or biopsy.

Participants who are alive after therapy reported along with a 95% confidence interval.

Here is the number of participants with treatment-related adverse events causing a delay of 4 weeks or more beyond planned surgery. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

National Cancer Institute (NCI)

Principal Investigator

20/21 participants were analyzed because one participant declined to participate before treatment started. And no participants were enrolled in Arm C.

Phase I/II M7824 (Days 1, 15)

M7824: M7824 (1200 mg) will be administered intravenously on day 1 and 15 to patients enrolled in arm 1-3 (all three arms).

Arm A, Cohort 1 Bintrafusp Alfa (M7824) 1200 mg (Days 1, 15)

Phase I/II M7824 + TriAd vaccine (ETBX-011, ETBX-051 and ETBX-061) (Days 1)

M7824: M7824 (1200 mg) will be administered intravenously on day 1 and 15 to patients enrolled in arm 1-3 (all three arms).

TriAd vaccine: TriAd vaccine (5 x 10e(11) viral particles (VP); subcutaneous injection) will be given on day 1 to patients enrolled in arm 2 and arm 3

Arm B,Cohort 1 M7824 1200mg+TriAdVaccine 5x10e^11viral Particles(ETBX-011,ETBX-051&ETBX-061) (Day 1)

Phase I/II No participants were enrolled on Arm C, Cohort 1. M7824 + TriAd vaccine (Day 1) + N-803 (Day 1) M7824: M7824 (1200 mg) will be administered intravenously on day 1 and 15 to patients enrolled in arm 1-3 (all three arms).

N803: N-803 (15 mcg/kg, subcutaneously) will be given on day 1 to patients enrolled in arm 3.

TriAd vaccine: TriAd vaccine (5 x 10e(11) viral particles (VP); subcutaneous injection) will be given on day 1 to patients enrolled in arm 2 and arm 3

Arm C, Cohort 1 M7824 1200mg + TriAd Vaccine 5x10e^11 Viral Particles (Day 1)+N-803 15mcg/kg (Day 1)

Participant was enrolled but not treated.

Enrolled But Not Treated

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Baseline characteristic data collected for one participant that was enrolled but not treated is reported here.

Dr. Jason Redman

Arm A, Cohort 1 Bintrafusp Alfa (M7824) (Days 1, 15)

20/21 participants were analyzed because one participant declined to participate before treatment started.

Number of Participants Who Experience a Pathologic Complete Response (pCR)

Number of Participants Who Experience Clinical to Pathologic Downstaging Upon Analysis of Resected Tumor After Completing Study Treatments

Proportion of Participants With a Complete Response (CR) + Partial Response (PR) Measured by Computed Tomography (CT) Imaging and the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Grade 3 Vasculitis

Grade 4 Pneumonitis

Number of Participants That Experienced Grade 3 or 4 Immune Related Adverse Events (irAEs)

1 year

2 years

Probability of Being Alive and Recurrence Free

20/21 participants were analyzed because one participant declined to participate before treatment started. The data reported is observed data.

Percentage of Participants Who Are Alive

Number of Participants With Treatment-related Adverse Events Causing a Delay of 4 Weeks or More Beyond Planned Surgery

Phase I/II No participants were enrolled on Arm C, Cohort 1.

M7824 + TriAd vaccine (Day 1) + N-803 (Day 1)

M7824: M7824 (1200 mg) will be administered intravenously on day 1 and 15 to patients enrolled in arm 1-3 (all three arms).

N803: N-803 (15 mcg/kg, subcutaneously) will be given on day 1 to patients enrolled in arm 3.

TriAd vaccine: TriAd vaccine (5 x 10e(11) viral particles (VP); subcutaneous injection) will be given on day 1 to patients enrolled in arm 2 and arm 3

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase II Lung Metcore - Preoperative Metformin for Lung Cancer	NCT03086733	Non Small Cell ... Lung Cancer	Metformin	18 Years - 90 Years	University Health Network, Toronto
Anti-PD-L1/TGF-beta Trap (M7824) Alone and in Combination With TriAd Vaccine and N-803 for Resectable Head and Neck Squamous Cell Carcinoma Not Associated With Human Papillomavirus Infection	NCT04247282	Head and Neck C... Head and Neck N...	M7824 N803 TriAd vaccine	18 Years -	National Institutes of Health Clinical Center (CC)

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