Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Lenvatinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma.

Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy.

Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles until disease progression, development of unacceptable toxicity or withdrawal of consent.

Eisai US Medical Services

The purpose of this study is to assess the objective response rate of lenvatinib in previously treated participants with American Joint Committee on Cancer (AJCC) unresectable Stage III or Stage IV melanoma and disease progression.

This was a Phase 2, multicenter, open-label, 2-cohort, 2-stage study that assessed the ORR of lenvatinib in previously treated participants with AJCC unresectable Stage III or Stage IV melanoma and disease progression. Cohort 1 enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma, and is referred to as Cohort 1 or V600E BRAF negative. Other less common BRAF activating mutations were allowed as long as the participant did not receive a BRAF-targeted therapy. Cohort 2 enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy, and is referred to as Cohort 2 or V600E BRAF positive. Eligible participants had measurable disease according to RECIST 1.1.

An Open-Label, 2-Cohort, Multicenter, Study of Lenvatinib in Previously Treated Subjects With Unresectable Stage III or Stage IV Melanoma

An Open-Label, 2-Cohort, Multicenter, Phase 2 Study of E7080 (Lenvatinib) in Previously Treated Subjects With Unresectable Stage III or Stage IV Melanoma

ORR, (ORR = CR + PR) was defined as the percentage of participants in each cohort who had a best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 for target lesions assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans and independent radiologic review (IRR). A BOR of CR required confirmation by a subsequent CR assessment at least 4 weeks later. A BOR of PR required confirmation by a subsequent assessment of CR or PR at least 4 weeks later. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to have a reduction in short axis to less than (\<)10 mm. PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

PFS was measured as the time from the date of first administration of study treatment until the date of first documentation of disease progression or date of death from any cause (whichever occurred first), as determined by IRR and Investigator based on RECIST v1.1. Disease progression per RECIST v1.1 was defined as at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was analyzed using Kaplan-Meier (1958) product-limit estimates. Data were presented with 2-sided 95% confidence interval (CI) when an adequate number of at risk participants warranted the estimates in the table below.

OS was defined as the length of time in months from the date of first administration of study drug until the date of death from any cause, and was based on the data cutoff date for each cohort. OS was analyzed using Kaplan-Meier (1958) product-limit estimates. Data were presented with 2-sided 95% CI when an adequate number of at risk participants warranted the estimates in the table below.

DCR, (DCR = CR + PR + SD) was defined as the percentage of participants who had a BOR of CR or PR or stable disease (SD) based on RECIST v1.1 for target lesions assessed by MRI/CT and IRR. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (target or non-target) had to have a reduction in short axis to \<10 mm.; PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; Overall Response (OR) = CR + PR. SD defined as reduction in tumor volume of \< 30% or an increase in the volume of 1 or more measurable lesions of \< 25% without the appearance of any new lesions which was neither tumor shrinkage corresponding to PR nor tumor expansion corresponding to disease progression. BOR of SD, time from first administration of study drug until date of documented SD needed to be \>=7 weeks based on IRR and Investigator's assessment.

CBR, (CBR = CR + PR + durable SD rate) was defined as the percentage of participants who had a BOR of CR or PR or durable SD (dSD, SD lasting \>=23 weeks) based on RECIST v1.1 for target lesions assessed by MRI/CT, IRR and Investigator's assessment. A BOR of CR required confirmation by a subsequent CR assessment at least 4 weeks later. A BOR of PR required confirmation by a subsequent assessment of CR or PR at least 4 weeks later. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (target or non-target) had to have a reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; OR = CR + PR. A BOR of dSD, the time from the first administration of study drug until the date of documented dSD needed to be ≥23 weeks based on IRR and Investigator's assessment.

Safety was assessed by monitoring and recording all AEs including all Common Terminology Criteria for Adverse Events (CTCAE) grades and SAEs; regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECGs), and multi-gated acquisition (MUGA) scans or echocardiogram.

Blood samples were drawn at specific time points. Utilizing a standard protocol, the deoxyribonucleic acid (DNA) from whole blood was extracted and analyzed for specific biomarkers of absorption, distribution, metabolism, and excretion of lenvatinib. Some of the biomarkers analyzed included; Angiopoietin, Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), FMS Like Tyrosine Kinase 3 Ligand (Flt3l) Granulocyte Colony Stimulating Factor (G-CSF), Granulocyte Macro Colony Stimulating Factor (GM-CSF), Interleukin 1 Receptor Antagonist (IL-1RA), Interferon (IFN), Macrophage Inflammatory Protein (MIP) 1 alpha, Platelet Derived Growth Factor (PDGF), Stromal Cell Derived Factor (SDF) 1 alpha, Interleukin (IL), Transforming Growth Factor (TGF), Tumor Necrosis Factor (TNF), Vascular Endothelial Growth Factor (VEGF).

Blood samples for the quantification of lenvatinib in plasma were obtained and processed using a standardized protocol. The lower limit of quantification was 0.25 ng/mL. Pharmacokinetic (PK) analysis was conducted using nonlinear mixed effects modeling. Descriptive statistics were used to summarize lenvatinib plasma concentration data.

Eisai Inc.

Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.

Cohort 1 (V600E BRAF Negative)

Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.

Cohort 2 (V600E BRAF Positive)

Total

Age, Continuous

Female

Male

Sex/Gender, Customized

Unresectable Stage III

Unresectable Stage IV

American joint committee on cancer (AJCC) (8th edition) staging system for melanoma tumor categorize the tumor in five stages: Stage 0: no evidence of primary tumor/early cancer that has not spread to neighboring tissue; Stage 1: tumor thickness measurements less than or equal to (\<=)1.0 millimeter (mm); Stage 2: tumor thickness measurements greater than (\>)1.0 mm to 2.0 mm; Stage 3: tumor thickness measurements \>2.0 mm to 4.0 mm; Stage 4: tumor thickness measurements \>4.0 mm. Higher stage of tumor shows worse outcomes.

AJCC Melanoma Tumor, Node, Metastasis (TNM) Stage at Study Entry

Eisai Medical Services

Full Analysis Set (Intent-to-Treat \[ITT\] Analysis Set) included all participants who received at least 1 dose study drug.

Objective Response Rate (ORR)

Determined by IRR

Determined by Investigator

Full Analysis Set (ITT Analysis Set) included all participants who received at least 1 dose study drug.

Progression Free Survival (PFS)

Overall Survival (OS)

Disease Control Rate (DCR)

Clinical Benefit Rate (CBR)

SAEs

Safety Analysis Set included those participants who received at least 1 dose of study drug and had at least 1 post baseline safety evaluation.

Number of Participants With Adverse Events (AEs)/ Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib

Angiopoietin 2 76 C1D15

Angiopoietin 2 76 C2D1

Angiopoietin 2 76 C3D1

Angiopoietin 2 76 V98

Angiopoietin 2 90 C1D15

Angiopoietin 2 90 C2D1

Angiopoietin 2 90 C3D1

Angiopoietin 2 90 V98

Angiopoietin 1 C1D15

Angiopoietin 1 C2D1

Angiopoietin 1 C3D1

Angiopoietin 1 V98

Angiopoietin 2 C1D15

Angiopoietin 2 C2D1

Angiopoietin 2 C3D1

Angiopoietin 2 V98

CD40 Ligand C1D15

CD40 Ligand C2D1

CD40 Ligand C3D1

CD40 Ligand V98

EGF 2 C1D15

EGF 2 C2D1

EGF 2 C3D1

EGF 2 V98

EGF 59 C1D15

EGF 59 C2D1

EGF 59 C3D1

EGF 59 V98

EGF 80 C1D15

EGF 80 C2D1

EGF 80 C3D1

EGF 80 V98

Eotaxin-4 C1D15

Eotaxin-4 C2D1

Eotaxin-4 C3D1

Eotaxin-4 V98

FGF 2 C1D15

FGF 2 C2D1

FGF 2 C3D1

FGF 2 V98

FGF 23 C1D15

FGF 23 C2D1

FGF 23 C3D1

FGF 23 V98

FGF 4 C1D15

FGF 4 C2D1

FGF 4 C3D1

FGF 4 V98

FGF Basic Form C1D15

FGF Basic Form C2D1

FGF Basic Form C3D1

FGF Basic Form V98

Flt3l C1D15

Flt3l C2D1

Flt3l C3D1

Flt3l V98

Fractalkine C1D15

Fractalkine C2D1

Fractalkine C3D1

Fractalkine V98

G-CSF C1D15

G-CSF C2D1

G-CSF C3D1

G-CSF V98

GM-CSF C1D15

GM-CSF C2D1

GM-CSF C3D1

GM-CSF V98

Growth Regulated Oncogene C1D15

Growth Regulated Oncogene C2D1

Growth regulated oncogene C3D1

Growth regulated oncogene V98

Hepatocyte Growth Factor C1D15

Hepatocyte Growth Factor C2D1

Hepatocyte Growth Factor C3D1

Hepatocyte Growth Factor V98

Interferon Gamma C1D15

Interferon Gamma C2D1

Interferon Gamma C3D1

Interferon Gamma V98

Interleukin 1 alpha C1D15

Interleukin 1 alpha C2D1

Interleukin 1 alpha C3D1

Interleukin 1 alpha V98

Interleukin 1 Beta C1D15

Interleukin 1 Beta C2D1

Interleukin 1 Beta C3D1

Interleukin 1 Beta V98

IL-1RA C1D15

IL-1RA C2D1

IL-1RA C3D1

IL-1RA V98

Interleukin 12 (p40) C1D15

Interleukin 12 (p40) C2D1

Interleukin 12 (p40) C3D1

Interleukin 12 (p40) V98

Interleukin 12 (p70) C1D15

Interleukin 12 (p70) C2D1

Interleukin 12 (p70) C3D1

Interleukin 12 (p70) V98

The Safety Analysis set was used and included all participants who received at least one dose of lenvatinib and had at least 1 postbaseline safety evaluation. Number analyzed (n) signifies participants who were evaluable at specific time points for this outcome measure.

Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood

C1D1 Pre-dose

C1D1 Post-dose

C1D15 Pre-dose

C1D15 Post-dose

C2D1 Pre-dose

C2D1 Post-dose

The PK analysis set was used for analysis and included all participants who received at least one dose of lenvatinib and had at least one quantifiable lenvatinib concentration. Number analyzed (n) signifies participants who were evaluable at specific time points for this outcome measure.

Summary of Plasma Concentration of Lenvatinib

Overall Study

Temozolomide

Tubulin Modulators

Antineoplastic Agents, Alkylating

Alkylating Agents

Starting dose of TPI 287 90 mg/m\^2 IV on Days 1, 8, 15 + Temozolomide (Temodar) PO at 85 mg/m\^2 on Days 1-5.

Starting dose cycle 1, 90 mg/m2 by vein (IV) on Days 1, 8, 15 (+/- 1 day)

TPI 287

Starting dose cycle 1, 85 mg/m\^2 by mouth (PO) daily, Day 1 to 5.

Temodar (Temozolomide)

Rodabe N Amaria, MD

The goal of the Phase I portion of this study is to find the highest tolerable dose of TPI 287 that can be given in combination with Temodar (temozolomide) to patients with metastatic melanoma.

The goal of the Phase II portion of this study is to learn if TPI 287, given in combination with temozolomide, can control metastatic melanoma. The safety of this combination will also be studied. NOTE: Study stopped before progressing to Phase II portion.

Study Drugs:

TPI 287 is designed to block tumors from growing by preventing cancer cells from dividing.

Temozolomide is designed to kill cancer cells by causing breaks in the DNA (genetic material) of the cell.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you joined this study. Up to 8 groups of 6 participants will be enrolled in the Phase I portion of the study, and up to 64 participants will be enrolled in Phase II.

If you are enrolled in the Phase I portion, the dose of TPI 287 and temozolomide you receive will depend on when you joined this study. The first group of participants will receive the lowest dose level of TPI 287 and temozolomide. Each new group will receive a higher dose of TPI 287 and temozolomide than the group before it, if no intolerable side effects were seen. If any of these participants have a dose limiting toxicity, 6 additional participants will be added at the same dose. If a dose limiting toxicity occurs again, the dose level below this will be considered the maximum tolerated dose.

If any participant experiences a life threatening side effect, no additional participants will be enrolled into that dose level and no higher doses will be given. An additional 3 participants will be treated at the dose level below the one with life threatening toxicity. Once the maximum tolerated dose of the combination is found, Phase II of the study will open.

If you are enrolled in the Phase II portion, you will receive the drug combination at the highest dose that was tolerated in the Phase I portion

Central Venous Catheter (CVC):

You will have a CVC placed. A CVC is a sterile, flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure.

Study Drug Administration:

You will receive TPI 287 by vein over 1 hour (+/- 10 minutes) on Days 1, 8, and 15 (+/- 1 day) of each 28 day study cycle. Before you receive each dose of TPI 287, you will receive dexamethasone, Benadryl (diphenhydramine), and Pepcid (famotidine) by vein to help prevent allergic reaction. You will also receive drugs to prevent nausea and vomiting. Your vital signs will be measured before and 30 minutes following the end of the infusion of TPI 287. Your vitals will be measured more often, if needed.

You will take temozolomide tablets by mouth on Days 1-5 at bedtime. You should not eat for at least 1 hour before and 1 hour after taking temozolomide.

Study Visits:

Before each cycle, your performance status will be recorded and you will have a physical exam. You will also be asked about any symptoms you may be experiencing and any drugs you are taking.

On Days 1, 8, and 14 of each cycle:

-Blood (about 1 teaspoon) will be drawn for routine tests before you receive TPI 287.

On Day 22 of each cycle:

-Blood (about 1 teaspoon) will be drawn for routine tests.

Every 8 weeks, you will have a CT scan or MRI scan to check the status of the disease. If you have brain metastasis, you will have an MRI of the brain every 4 weeks. If you do not have brain metastasis, you will have MRI of the brain every 8 weeks.

Length of Study:

You will continue taking the study drugs for as long as you are benefitting. You will be taken off study if the disease gets worse or intolerable side effects occur.

End-of-Treatment Visit:

About 4 weeks after you stop taking TPI 287 in combination with Temozolomide, you have an end-of-study visit. At this visit, the following tests and procedures will be performed:

* You will have a physical exam.
* You will be asked about any complications or side effects you may be experiencing.
* Blood (about 2 tablespoons) will be drawn for routine tests.
* If your doctor thinks it is needed, you will have a CT scan or MRI scan to check the status of the disease.

This is an investigational study. TPI 287 is not FDA approved or commercially available. At this time, TPI 287 is being used in research only. Temozolomide is FDA approved and commercially available for primary brain cancer. The use of temozolomide in combination with TPI 287 is investigational.

Up to 106 patients will take part in this study. All patients will be enrolled at MD Anderson.

A Phase I Study of TPI 287 - Temozolomide Combination in Melanoma

A Phase I/II Open-Label Study TPI 287 in Combination With Temozolomide in Patients With Metastatic Melanoma

MTD is highest dose level in which 6 patients treated with at most 1 experiencing dose limiting toxicity (DLT).

Maximum Tolerated Dose (MTD), measured by clinical and laboratory adverse events.

Response rate provided along with a 95% credible interval. Logistic regression models used to assess the association between progression-free survival at 6 months and covariates of interest. Additionally, Cox proportional hazards regression models will be fit to model the association between progression-free survival and the same covariates. Simon's minimax two-stage design used to evaluate the response rate.

Cortice Biosciences, Inc.

M.D. Anderson Cancer Center

Pharmaceutical Solutions

Ipilimumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

IV solution, IV, 10 mg/kg, Q 3 wks for 12 wks then Q 12 wks, 48+ weeks depending on response.

ipilimumab (MDX-010, BMS-734016)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
An Open-Label, 2-Cohort, Multicenter, Study of Lenvatinib in Previously Treated Subjects With Unresectable Stage III or Stage IV Melanoma	NCT01136967	Unresectable St... Stage IV Melano...	Lenvatinib	18 Years - 99 Years	Eisai Inc.
A Phase I Study of TPI 287 - Temozolomide Combination in Melanoma	NCT01067066	Melanoma	TPI 287 Temodar (Temozo...	15 Years -	M.D. Anderson Cancer Center
A Single Arm Study of Ipilimumab Monotherapy in Patients With Previously Treated Unresectable Stage III or IV Melanoma	NCT00289627	Melanoma	ipilimumab (MDX...	18 Years -	Bristol-Myers Squibb
A Phase I Study of TPI 287 - Temozolomide Combination in Melanoma	NCT01067066	Melanoma	TPI 287 Temodar (Temozo...	15 Years -	M.D. Anderson Cancer Center
An Open-Label, 2-Cohort, Multicenter, Study of Lenvatinib in Previously Treated Subjects With Unresectable Stage III or Stage IV Melanoma	NCT01136967	Unresectable St... Stage IV Melano...	Lenvatinib	18 Years - 99 Years	Eisai Inc.

Spots Global Cancer Trial Database for unresectable stage iii