Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Rare Diseases

Lung Neoplasms

Carcinoma

Small Cell Lung Carcinoma

Carcinoma, Neuroendocrine

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Adenocarcinoma

Neoplasms, Nerve Tissue

Small Cell Lung Cancer

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Etoposide

Cisplatin

Belinostat

Etoposide phosphate

Histone Deacetylase Inhibitors

Enzyme Inhibitors

6 cycles of belinostat 400 mg/m2/24h X2 administered by CIV

6 cycles 80 mg/m2 IV daily X3 beginning day 2.

Anish Thomas, M.D.

BACKGROUND:

* The histone deacetylase (HDAC) inhibitors are a novel class of anticancer agent. These agents lead to the increased acetylation of both histone and non-histone proteins, which leads to rapid cell death in many tumor models. It is thought that the cell death observed with this class of agents may be mediated, in part, through the selective acetylation of histone proteins resulting in increased expression of specific genes.
* For solid tumors in general, cell death in preclinical models has not translated to activity in patients. For this reason, studies increasingly have combined chemotherapy with HDAC inhibitors to achieve additive and potentially synergistic effects on cancer cells.
* This protocol will study a continuous infusion of the HDAC inhibitor belinostat in combination with cisplatin and etoposide for patients with advanced cancer.

OBJECTIVES:

* To determine a safe and tolerable phase 2 dose for the combination of belinostat with cisplatin and etoposide.
* Evaluate molecular markers of HDAC inhibition.

ELIGIBILITY:

* The protocol will be open to all patients with recurrent or advanced cancer (small-cell lung cancer and other advanced cancers) for whom standard therapy offers no curative potential.
* Age greater than or equal to 18 years
* ECOG Performance Status 0-2

DESIGN:

* The study will begin with belinostat 400 mg/m (2)/24h administered by continuous IV infusion on days 1 and 2, cisplatin at 80 mg/m (2) IV on day 2, and etoposide at 100 mg/m (2) IV daily times 3 on days 2 - 4. Dose escalation of belinostat will follow according to traditional 3 patient cohorts.
* Treatment schedule and dose escalation schemata.

BACKGROUND:

* The histone deacetylase (HDAC) inhibitors are a novel class of anticancer agent. These agents lead to the increased acetylation of both histone and non-histone proteins, which leads to rapid cell death in many tumor models. It is thought that the cell death observed with this class of agents may be mediated, in part, through the selective acetylation of histone proteins resulting in increased expression of specific genes.
* For solid tumors in general, cell death in preclinical models has not translated to activity in patients. For this reason, studies increasingly have combined chemotherapy with HDAC inhibitors to achieve additive and potentially synergistic effects on cancer cells.
* This protocol will study a continuous infusion of the HDAC inhibitor belinostat in combination with cisplatin and etoposide for patients with advanced cancer.

OBJECTIVES:

* To determine a safe and tolerable phase 2 dose for the combination of belinostat with cisplatin and etoposide.
* Evaluate molecular markers of HDAC inhibition.
* To explore the results of administering the dose of belinostat based on the patients' UGT1A1 \*28 or \*60 genotype, which is a characteristic that may be associated with toxicity.

ELIGIBILITY:

* The protocol will be open to all patients with recurrent or advanced cancer (small-cell lung cancer and other advanced cancers) for whom standard therapy offers no curative potential.
* Age greater than or equal to 18 years
* ECOG Performance Status 0-2

DESIGN:

* The study will begin with belinostat 400 mg/m (2)/24h administered by continuous IV infusion on days 1 and 2, cisplatin at 60 mg/m(2) IV on day 2, and etoposide at 80 mg/ (2) IV daily times 3 on days 2 - 4. Dose escalation of belinostat will follow according to traditional 3 patient cohorts.
* With Amendment M, dosing will be based on UGT1A1 status, at either 400 mg/m(2) or

  600 mg/m(2)

A Phase I Study of Belinostat in Combination With Cisplatin and Etoposide in Adults With Small Cell Lung Carcinoma and Other Advanced Cancers

A Phase I Study of Belinostat in Combination With Cisplatin and Etoposide in Adults With a Focus on Small Cell Lung Cancer and Other Cancers of Neuroendocrine Origin

National Cancer Institute (NCI)

Pembrolizumab

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Immunoglobulin G

Immunoglobulins, Intravenous

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients will receive CDX-1440, TCR-T, and pembrolizumab.

TCR-transduced T cells

Recombinant fully human IgG2κ monoclonal antibody

CDX-1140

Humanized immunoglobulin G4 (IgG4) monoclonal antibody

Rom Leidner, MD

Eric Tran, PhD

This is a phase I/Ib study of adoptively transferred T-cell receptor gene-engineered T cells (TCR-T) targeting tumor-specific antigens, with in vivo CD40 activation and PD-1 blockade, for patients with incurable cancers. The study design is a safety lead-in TCR-T with CD40/PD-1 (3+3), followed by Simon's Two-Stage expansion design, 80% power and 5% one-sided alpha: stage-one futility assessment at n = 10; stage-two assessment at n = 22, (accrual up to 24 to allow for potential study drop-out).

Patients will be infused with T cells engineered to express TCRs targeting one to five tumor-specific antigens expressed by their autologous tumor. The number of T cells infused will range from 1e9 to 1e11. Monoclonal antibodies targeting PD-1 (pembrolizumab) and CD40 (CDX-1140, Celldex Therapeutics)43 will be administered, in that order, starting within 24 hours of cell infusion and re-administered at approximately 3 week intervals. Clinic visits will include longitudinal evaluation of toxicities and monitoring of immunological parameters. The presence or absence of replication competent retrovirus (RCR) will be evaluated for the first year following adoptive cell transfer, or longer, if there is evidence of RCR.

Tumor Response assessment by RECIST 1.1 is performed every 9-12 weeks. Study treatment continues until progression. Option repeat TCR-T infusion is allowed and in addition may incorporate preconditioning chemotherapy using a de-intensified non-myeloablative (NMA) regimen consisting of a single dose of gemcitabine and a single dose of either cyclophosphamide or epirubicin, designed to elicit immunogenic cell death and transient lymphopenia.

The primary objective of this study is to determine the safety of the adoptive transfer of TCR-gene engineered T cells targeting TSA in combination with CD40 and PD-1 immunotherapy. The secondary objective is to determine whether this therapy can mediate objective clinical responses as determined by objective criteria (e.g. RECIST 1.1). The study will also characterize the differentiation and functional state of the TCR-gene modified T cells before and after cell therapy and monitor their persistence in the patient after treatment. Up to 24 patients will be enrolled in this study. Based on published trials treating patients with TCR-transduced T cells, adverse events such as fever, chills, dyspnea, hypotension, fatigue, edema, rash, and rarely acute cytokine release syndrome, may occur.

Clinical and immunological data will be analyzed which will determine whether this therapy is safe and effective, and whether there are biomarkers or immunological signatures that correlate to efficacy and/or lack of efficacy. This data will determine whether additional studies are warranted.

Hotspot TCR-T: A Phase I/Ib Study of Adoptively Transferred T-cell Receptor Gene-engineered T Cells (TCR-T)

Hotspot TCR-T: A Phase I/Ib Study of Adoptively Transferred T-cell Receptor Gene-engineered T Cells (TCR-T) Targeting Tumor-Specific Neoantigens, With in Vivo CD40 Activation and PD-1 Blockade, for Patients With Incurable Cancers (2020000584)

the time from the earliest date of disease response (CR or PR) until earliest date of disease progression or death due to any cause

percentage of subjects having CR, PR, or SD (with minimum duration \> 4 months)

Providence Health & Services

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase I Study of Belinostat in Combination With Cisplatin and Etoposide in Adults With Small Cell Lung Carcinoma and Other Advanced Cancers	NCT00926640	Carcinoma Neuro... Small Cell Lung... Malignant Epith...	Belinostat Cisplatin Etoposide	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)
A Phase I Study of Belinostat in Combination With Cisplatin and Etoposide in Adults With Small Cell Lung Carcinoma and Other Advanced Cancers	NCT00926640	Carcinoma Neuro... Small Cell Lung... Malignant Epith...	Belinostat Cisplatin Etoposide	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)
Hotspot TCR-T: A Phase I/Ib Study of Adoptively Transferred T-cell Receptor Gene-engineered T Cells (TCR-T)	NCT04520711	Malignant Epith...	TCR-transduced ... CDX-1140 Pembrolizumab	-	Providence Health & Services
Hotspot TCR-T: A Phase I/Ib Study of Adoptively Transferred T-cell Receptor Gene-engineered T Cells (TCR-T)	NCT04520711	Malignant Epith...	TCR-transduced ... CDX-1140 Pembrolizumab	-	Providence Health & Services

Spots Global Cancer Trial Database for malignant epithelial neoplasms