Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Carcinoma, Hepatocellular

Liver Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Immunomodulating Agents

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Daily x 3 doses on Day -3, -2, -1 300 mg/m2 IV infusion (200 mg/m2 in Dose Level -1)

CAR-T cell

Daily x 2 doses on Day -2 and -1 30 mg/m2 IV infusion administered following cyclophosphamide

Donna M Hrones, C.R.N.P.

Tim F Greten, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

A new cancer treatment takes a person s own T cells, modifies them in a laboratory so they can better fight cancer cells, and then gives them back to the person. Researchers want to see if this treatment can help people with a certain type of liver cancer.

Objective:

To see if a personalized immune treatment, anti-GPC3 CAR-T cells, is safe.

Eligibility:

Adults aged 18 years and older who have Glypican-3 (GPC3) positive HCC, a type of liver cancer.

Design:

Participants will be screened with the following:

Blood and urine tests

Medical history

Physical exam

Heart function tests

Review of their symptoms and their ability to perform their normal activities

Tumor biopsy

Imaging scan of the chest, abdomen, and pelvis

Participants will have leukapheresis. They may have an IV (intravenous catheter, a small tube put into an arm vein) inserted into each arm or get a central line. Blood will be removed. A machine will separate the white blood cells from their blood. The rest of their blood will be returned to them.

Participants will be admitted to the hospital for about 2 weeks. They will get the chemotherapy drugs fludarabine and cyclophosphamide by IV for 3 days. Then they will receive the modified white blood cells by IV.

Participants will have frequent blood draws. They will give blood and tumor samples for research.

Participants will have follow-up visits for the next 15 years. Then they will be contacted by email or phone for the rest of their life. If their disease does not get worse after 5 years, they will continue to be invited to do imaging studies every 6 months.

Background:

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second leading cause of cancer-associated mortality with an average life expectancy of 6-9 months

Despite the success of several studies showing efficacy in treating HCC, most clinical trials have failed to prove a survival advantage.

Adoptive T-cell therapy exploits the natural ability of T-cells to recognize and eliminate their target.

GPC3 is a cell surface protein that is expressed in nearly all HCC yet is undetectable in normal adult hepatic tissues.

We want to evaluate the role of GPC3 targeted chimeric antigen receptor (CAR)-T cells in advanced GPC3 expressing HCC.

Objective:

To determine the safety and feasibility of T-cells, expressing a novel humanized anti-GPC3 chimeric antigen receptor, in participants with advanced HCC, expressing GPC3.

Eligibility:

Histologically confirmed diagnosis of hepatocellular carcinoma

GPC3 positivity of \>= 25% by immunohistochemistry

At least 1 measurable lesion by RECIST v 1.1 criteria

Age \>= 18 years

Design:

We plan to conduct a phase I dose escalation designed clinical trial using CAR (hYP7)-T cells in participants with GPC3 expressing advanced hepatocellular carcinoma.

Participants will undergo leukapheresis

Participants will receive a lymphocyte depleting chemotherapy conditioning regimen with the intent of enhancing the activity of the infused CAR-expressing T cells

Following the T cell infusion, there is a mandatory 9-day inpatient hospitalization to monitor for toxicity.

The participants will be closely monitored during the first year after cell infusion and followed for life.

GPC3 Targeted CAR-T Cell Therapy in Advanced GPC3 Expressing Hepatocellular Carcinoma (HCC)

Phase I Study of GPC3 Targeted CAR-T Cell Therapy in Advanced GPC3 Expressing Hepatocellular Carcinoma (HCC)

.All IPD recorded in the medical record will be shared with intramural investigators upon request.@@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP

Safety will be reported based on DLTs per dose level as well as reporting specific grades and types of toxicity encountered. Feasibility will be reported descriptively as the fraction of patients overall and per dose level who are able to receive sufficient CAR T cells as required for the specified dose level

Kaplan-Meier curve and 95% confidence interval for the median OS

BOR rate will be reported among the 12 participants at the final dose level, along with a 95% two-sided confidence interval

National Cancer Institute (NCI)

Respiratory Tract (Lung and Bronchial) Diseases

Skin and Connective Tissue Diseases

Gland and Hormone Related Diseases

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Lung Neoplasms

Carcinoma, Squamous Cell

Breast Neoplasms

Pancreatic Neoplasms

Cholangiocarcinoma

Lymphoma

Head and Neck Neoplasms

Sarcoma

Chordoma

Bile Duct Neoplasms

Biliary Tract Neoplasms

Bile Duct Diseases

Biliary Tract Diseases

Neoplasms, Germ Cell and Embryonal

Pancreatic Cancer

Bile Duct Cancer

Lymphosarcoma

Soft Tissue Sarcoma

Pharmaceutical Solutions

Dermatologic Agents

Antibodies

Pembrolizumab

Cisplatin

Ipilimumab

Immunoglobulins

Vinblastine

Coal Tar

Immunoglobulins, Intravenous

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

INT230-6 injections every 28 days for 5 sessions into only superficial tumors, low starting dose, low concentration per tumor.

Completed

INT230-6 injections every 28 days for 5 sessions into deep tumors, low starting dose, low drug concentration per tumor

Completed

INT230-6 injections every 2 weeks for 5 sessions into superficial tumors, medium starting dose, low drug concentration per tumor

Completed

INT230-6 injections every 2 weeks for 5 sessions into superficial or deep tumors, moderately high starting dose, high drug concentration per tumor

Completed

INT230-6 injections every 2 weeks for 5 sessions into superficial or deep tumors, high starting dose, moderate drug concentration per tumor, higher number of tumors to be treated per session than EC

Completed

INT230-6 injections every 2 weeks for 5 sessions with the possibility for INT230-6 retreatment into superficial tumors, with addition of anti-PD-1 antibody Keytruda (pembrolizumab) dosed concurrently starting at Day 1 every 3 weeks for two years for selected cancer types.

Completed

INT230-6 injections every 2 weeks for 5 sessions at fixed maximal dose into superficial or deep tumors, unlimited number of tumors to be treated per session with retreatment once every 9 weeks for two years.

Completed

INT230-6 per the dosing of cohort EC3 combined with Keytruda (pembrolizumab) dosed per DEC concurrently starting at Day 1 for selected cancers.

Completed

INT230-6 per the EC3 regimen combined with Yervoy (ipilimumab) dosed concurrently starting at Day 1 every 3 weeks for four treatments for selected cancer types.

Completed

INT230-6 is clear sterile solution administered by injection directly into the tumor to be treated.

The product contains a cell permeation agent with cisplatin and vinblastine sulfate at fixed concentrations.

The drug is stored frozen and must be dosed at room temperature.

The drug dose to be administered is set by the tumor volume of the target lesions - not the subject's body surface area

INT230-6

The anti-PD-1 antibody will be added concomitantly with INT230-6 as noted in cohort DEC and DEC2

anti-PD-1 antibody

The anti-CTLA-4 antibody will be added concomitantly with INT230-6 as noted in cohort FEC

anti-CTLA-4 antibody

Ian B. Walters, M.D.

Lillian Siu, M.D., FRCP

Anthony El-Khoueiry, M.D.

Anthony J. Olszanski, M.D., RPh

Nilofer Azad, M.D.

Giles F Whalen, M.D.

Matthew Ingham, M.D.

Luis Camacho, M.D.

This study evaluates the intratumoral administration of escalating doses of a novel, experimental drug, INT230-6. The study is being conducted in patients with several types of refractory cancers including those at the surface of the skin (breast, squamous cell, head and neck) and tumors within the body such (pancreatic, colon, liver, lung, etc.). Sponsor also plans to test INT230-6 in combination with anti-PD-1 and anti-CTLA-4 antibodies.

INT230-6 is comprised of a 3 agents in a fixed ratio - a cell permeation enhancer and two, potent anti-cancer payloads (cisplatin and vinblastine sulfate). The penetration enhancer facilitates dispersion of the two drugs throughout injected tumors and enables increased diffusion into cancer cells. (Nonclinical safety studies showed no findings following drug injection into healthy tissues.)

Historically physicians administer the two active drugs comprising INT230-6 by intravenous (IV) infusion to achieve a systemic blood level at the limit of tolerability. The objective is destroy both visible tumors and unseen circulating cancer cells (micro-metastases). Unfortunately, dosing drugs IV delivers only a small amount with a low concentration at the tumor site. This approach especially for late stage cancers is not highly effective and often quite toxic to the patient.

Attempts at direct intratumoral injection with chemotherapeutic agents have not shown the ability to treat the injected tumor, non-injected tumors or micro-metastases. This lack of efficacy for local administration is due possibly to poor dispersion and a lack of cell uptake of the agents.

Due to the use of the novel cell penetration enhancing agent INT230-6 treatment demonstrates strong efficacy in animals having large tumors. The Sponsor's in vivo, non-clinical data shows that INT230-6 thoroughly saturates and kills injected tumors. In addition, the drug induces an adaptive (T-cell mediated) immune response that attacks not only the injected tumor, but non-injected tumors and unseen micro-metastases. Cured animals become permanently immunized against the type of cancer that INT230-6 eliminates.

Clinical trial IT-01 seeks to determine the safety and potential efficacy of dosing INT230-6 directly into several different types of cancers. In addition animal studies showed a strong synergy of INT230-6 with immune modulation agents. Thus as part of study IT-01 the Sponsor seeks to understand the safety and efficacy of INT230-6 when administered in combination with immuno-therapeutic agents such as antibodies that target Programmed Cell Death (PD-1 or anti-PD-1) and Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4 or anti-CTLA-4) receptors.

This study seeks to understand whether tumor regression can be achieved and patient outcomes improved.

There were 6 cohorts in the escalation portion of the protocol. Five dosed INT230-6 alone and one was combined with pembrolizumab. Cohorts A and B1 treated superficial tumors at a 1:4 ratio of drug to tumor with a low tumor load once per month. Cohort EA was similar to cohort A with INT230-6 every 2 weeks. Cohort EC escalated the total and maximal dose per any one tumor to a ratio of 1:2 \& dosed every two weeks. Cohort EC2 explored a drug load ratio of 1:3 and escalated the dose per tumor further. Cohort DEC combined INT230-6 with a fixed amount of pembrolizumab.

On-going, non-escalation cohorts include 1) monotherapy INT230-6 cohort (EC3) dosed every two weeks 2) INT230-6 in a combination with pembrolizumab (DEC2) and 3) INT230-6 in combination with ipilimumab (FEC). Other specific regimens or combinations of INT230-6 may be designated by the Study Steering Committee.

There is no masking and all patients will receive INT230-6 treatments.

A Phase 1/2 Safety Study of Intratumorally Dosed INT230-6

A Phase 1/2 Safety Study of Intratumorally Administered INT230-6 in Adult Subjects With Advanced Refractory Cancers

Characterize response in non-injected lesions (up to 5) using length (cm) as the key parameter for measurement.

Evaluate various tumor and anti-tumor immune response biomarkers from blood, tumor tissue that may correlate with tumor response. Flow and tissue panels may include Live-Dead, CD3, CD4, CD8, FoxP3, Ki-67, ICOS, DAPI, PD-1, LAG-3, TIM-3, CTLA-4 and analysis of blood serum cytokine such as Th1/Th2, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 p70, IL-13, and TNF-α.

Evaluate overall response by iRECIST including survival

The primary objective is to assess the safety and tolerability of single and multiple intratumoral doses of INT230-6 in subjects with advanced or recurrent malignancies. This will be assessed by the rate of ≥ grade 3 AE's attributed to INT230-6 and not the underlying disease.

All recorded adverse events will be listed and tabulated by system organ class, preferred term, and dose and coded according to the most current version of MedDRA. The incidence of adverse events will be tabulated and reviewed for potential significance and clinical importance.

Adverse Events will be summarized for all reported data and by study period: a) up to and including 28 days post last dose of initial treatment, and b) from first dose of re-initiation of treatment, for subjects who re-initiate study therapy while in follow-up, up to 28 days post-dose of the last re-treatment dose.

Assess the preliminary efficacy of INT230-6 by measuring the disease control rate (CR+PR+SD) as assessed by iRECIST.

Assess INT230-6's effect on tumors by measuring the length, width and height (centimeters) of injected tumors during the dosing and afterward.

Characterize the peak plasma profile for the three INT230-6 components after single and then multiple IT tumor site injections for safety purposes. This has been completed.

Characterize the pharmacokinetic AUC profile of each of the three INT230-6 components for AUC after single IT tumor site injection for safety purposes. This has been completed.

Characterize the half life of each of the three INT230-6 components after single and multiple IT tumor site injections for safety purposes. This has been completed.

Merck Sharp & Dohme LLC

Bristol-Myers Squibb

Intensity Therapeutics, Inc.

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Small Cell Lung Carcinoma

Glomerulonephritis, Membranous

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Small Cell Lung Cancer

Membranous Nephropathy

Adjuvants, Immunologic

MGN1703, solution in Dulbecco's Phosphate-Buffered Saline (DPBS), 2 mL of 60 mg/4 mL (15 mg/mL), administered SC at 2 application sites twice weekly

MGN1703

Usual Standard of Care according to local investigators practise, e.g. Treatment break continous treatment and other

Standard of care

Veerle Surmont, MD

Georg Pall, MD

Evaluation of efficacy and safety of MGN1703 administered twice weekly subcutaneously (SC) as maintenance treatment in patients with extensive disease small cell lung cancer (SCLC) who achieved at least a partial response (PR) following platinum-based first-line therapy.

Randomized Study of Maintenance Therapy With MGN1703 in Patients With SCLC

Randomized Clinical Study of Maintenance Therapy With Immunomodulator MGN1703 in Patients With Extensive Disease Small Cell Lung Cancer After Platinum-Based First-Line Therapy

Progression-free survival is the time after randomization to either disease progression (PD), measured using RECIST 1.1 and irRC criteria and confirmed via centralized review or death

The primary efficacy endpoint is the OS which is defined as the time interval starting with the randomization and lasting until death (=event) or until the date of last information available from the patient.

The secondary efficacy endpoint OS1 is defined as the time interval starting at the first cycle of induction therapy and lasting until death (=event) or until the date of last information available from the patient.

OS1 will be estimated by Kaplan-Meier estimates. The comparison between the treatment groups will be performed using the log-rank test with a significance level of α = 2.5% for the 1-sided test. The OS1 will be presented as Kaplan-Meier figures also.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
GPC3 Targeted CAR-T Cell Therapy in Advanced GPC3 Expressing Hepatocellular Carcinoma (HCC)	NCT05003895	Hepatocellular ... Hepatocellular ... Metastatic Hepa...	Cyclophosphamid... CAR-T cell Fludarabine	18 Years -	National Institutes of Health Clinical Center (CC)
A Phase 1/2 Safety Study of Intratumorally Dosed INT230-6	NCT03058289	Breast Cancer Head and Neck C... Squamous Cell C... Lymphoma Pancreatic Canc... Liver Cancer Colon Cancer Lung Cancer Bile Duct Cance... Chordoma of Sac... Sarcoma	INT230-6 anti-PD-1 antib... anti-CTLA-4 ant...	18 Years -	Intensity Therapeutics, Inc.
GPC3 Targeted CAR-T Cell Therapy in Advanced GPC3 Expressing Hepatocellular Carcinoma (HCC)	NCT05003895	Hepatocellular ... Hepatocellular ... Metastatic Hepa...	Cyclophosphamid... CAR-T cell Fludarabine	18 Years -	National Institutes of Health Clinical Center (CC)
A Phase 1/2 Safety Study of Intratumorally Dosed INT230-6	NCT03058289	Breast Cancer Head and Neck C... Squamous Cell C... Lymphoma Pancreatic Canc... Liver Cancer Colon Cancer Lung Cancer Bile Duct Cance... Chordoma of Sac... Sarcoma	INT230-6 anti-PD-1 antib... anti-CTLA-4 ant...	18 Years -	Intensity Therapeutics, Inc.
Randomized Study of Maintenance Therapy With MGN1703 in Patients With SCLC	NCT02200081	Small Cell Lung...	MGN1703 Standard of car...	18 Years -	Mologen AG
Randomized Study of Maintenance Therapy With MGN1703 in Patients With SCLC	NCT02200081	Small Cell Lung...	MGN1703 Standard of car...	18 Years -	Mologen AG

Spots Global Cancer Trial Database for immuno therapy