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

The Initial Escalation Stage will enroll approximately 30 patients with advanced nonhematologic malignancies. TAK-733 will be administered orally in 28-day treatment cycles consisting of intermittent dosing with 21 days of continuous treatment, followed by a rest period of 7 days.

The Expansion Stage will enroll approximately 30 patients with advanced metastatic melanoma. The recommended phase 2 dose determined in the Initial Escalation Stage of TAK-733 will be administered orally in 28-day treatment cycles consisting of intermittent dosing with 21 days of continuous treatment, followed by a rest period of 7 days.

TAK-733

Medical Monitor

The purpose of this study is to evaluate the safety, pharmacokinetics, pharmacodynamics and maximum tolerated dose of TAK-733 in patients with advanced, nonhematologic tumors. The expansion stage of the study will evaluate evidence of antitumor activity of TAK-733 in patients with advanced metastatic melanoma.

Study of TAK-733 in Adult Patients With Advanced Nonhematologic Malignancies

A Multicenter, Open-label, Dose-escalation, Phase I Study of TAK-733, an Oral MEK Inhibitor, in Adult Patients With Advanced Nonhematologic Malignancies

Millennium Pharmaceuticals, Inc.

All Drugs and Chemicals

Antineoplastic Agents

Anti-Infective Agents

Lipid Regulating Agents

Vaccines

Ipilimumab

Isoniazid

BCG Vaccine

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Antitubercular Agents

Anti-Bacterial Agents

Hypolipidemic Agents

Antimetabolites

Adjuvants, Immunologic

Immunologic Factors

Patients with an induration \<10 mm in diameter after the baseline PPD reactivity test received BCG (IL) on Day 1, followed by isoniazid (orally, daily) starting 28 days after the BCG injection and continuing for 4 weeks, and ipilimumab (IV) administered every 3 weeks starting 5 weeks after the BCG injection and continuing for a total of 4 doses.

Patients with an induration \<10 mm in diameter after the baseline PPD reactivity test were to receive BCG (IL) on Day 1, followed by isoniazid (orally, daily) starting 28 days after the BCG injection and continuing for 4 weeks, and ipilimumab (IV) administered every 3 weeks starting 5 weeks after the BCG injection and continuing for a total of 4 doses.

Patients with an induration ≥10 mm in diameter after the baseline PPD reactivity test were to receive BCG (IL) on Day 1, followed by isoniazid (orally, daily) starting 28 days after the BCG injection and continuing for 4 weeks, and ipilimumab (IV) administered every 3 weeks starting 5 weeks after the BCG injection and continuing for a total of 4 doses.

BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.

Bacillus Calmette-Guérin (BCG) vaccine

Ipilimumab was to be administered as a 90-minute IV infusion at a dose of 3 mg/kg every 3 weeks (± 3 days) on Days 36, 57, 78, and 99.

Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.

Jonathan Cebon, MD, PhD

This was a Phase 1, open-label, dose-escalation, single-center study in patients with histologically confirmed Stage III or IV melanoma and at least 3 metastatic cutaneous or subcutaneous lesions that were suitable and accessible for intralesional (IL) injection (1 lesion), biopsy (1 lesion), and response evaluation (1 lesion). The primary objective was to determine the safety of IL administration of bacillus Calmette-Guerin (BCG) followed by oral dosing with an antibiotic (isoniazid) and intravenous (IV) infusions of ipilimumab. Secondary objectives were to evaluate the clinical efficacy (induction of tumor response) and immunogenicity (induction of immune response against the tumors) of the combination regimen.

Patients were enrolled into one of two study cohorts depending on the induration noted after a baseline purified protein derivative (PPD) skin test to determine tuberculin reactivity. Cohort 1 comprised patients with an induration of \<10mm in diameter, and Cohort 2 comprised patients with an induration of ≥10mm. Enrollment was staggered by 3 weeks for each of the first 3 patients in Cohort 1, Group 1 to enable safety monitoring of each patient prior to exposure of additional patients.

In all cohorts, study treatment included BCG (200 µL volume) given IL on Day 1, isoniazid (300 mg) given orally daily from Days 29 to 56, and ipilimumab (3 mg/kg) given IV every 3 weeks (± 3 days) on Days 36, 57, 78, and 99. The dose of BCG varied by assigned treatment group: Cohort 1, Group 1 received 0.16 - 0.64 × 10\^6 colony-forming units (CFU); Cohort 1, Group 2 received 0.8 - 3.2 x 10\^6 CFU; Cohort 1, Group 3 was to receive 4.0 - 16.0 x 10\^6 CFU; and Cohort 2 was to receive 0.16 - 0.64 × 10\^6 CFU. Enrollment into Cohort 2 was to be initiated after the final patient in Cohort 1, Group 1 reached Week 7. Enrollment was then to proceed in parallel for Cohort 2 and Cohort 1, Groups 2 and 3.

Patients were monitored for safety, tumor response, and immunogenicity (cellular, humoral, and in situ immunity) for the duration of study participation.

Phase I Study of Intralesional Bacillus Calmette-Guerin (BCG) Followed by Ipilimumab in Advanced Metastatic Melanoma

A Phase I Study of Intralesional Bacillus Calmette-Guerin (BCG) and Followed by Ipilimumab Therapy in Patients With Advanced Metastatic Melanoma

Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Treatment-emergent adverse events (TEAEs) were reported based on clinical laboratory tests, physical examinations, and vital signs from pre-treatment through the study period. Dose-limiting toxicity (DLT) for BCG was defined as any ≥ Grade 3 local injection site reaction (ulceration or necrosis requiring operative intervention), and DLT for ipilimumab was defined as any toxicity that required dosing modifications in accordance with the recommendations in the local product labelling, or any ≥ Grade 3 hematologic or nonhematologic toxicity that was definitely, probably, or possibly related to the administration of ipilimumab.

Tumor responses were evaluated using computed tomography and clinical photography at Baseline, Weeks 6, 17, 21, and 30 (± 3-day window for each assessment), and at the end of the study. Tumor response was designated according to the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1). Per RECIST, target lesions are categorized as follows: Complete Response (CR): Disappearance of all target lesions (no evaluable disease); Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria.

Immune-related tumor responses were evaluated using computed tomography and clinical photography at Baseline, Weeks 6, 17, 21, and 30 (± 3-day window for each assessment), and at the end of the study. Tumor response was designated according to the immune-related Response Criteria (irRC) (Wolchok et al. Clin Cancer Res 2009;15:7412-20) into the following categories: immune-related complete response (irCR) requires disappearance of all lesions in two consecutive observations not less than 4 weeks apart; immune-related partial response (irPR) requires ≥ 50% decrease in tumor burden compared with baseline in two observations at least 4 weeks apart; immune-related stable disease (irSD) is assigned when neither a 50% decrease from baseline tumor burden nor a 25% increase in tumor burden from nadir can be established; immune-related progressive disease (irPD) requires a ≥ 25% increase from nadir in tumor burden at any single time point in two consecutive observations at least 4 weeks apart.

Bristol-Myers Squibb

Ludwig Institute for Cancer Research

AE documentation included onset/resolution dates, severity using the NCI CTCAE (version 4.0), seriousness, relationship to study drug, study drug action taken, treatment, and outcome. In summaries, treatment-related AEs included those with a "possible", "probable", or "definite" relationship to study drug; preferred terms were counted only once per patient at the maximum reported grade.

Patients with an induration \<10 mm in diameter after the baseline PPD reactivity test received BCG (IL, 200 µL volume) at a dose of 0.16 - 0.64 × 10\^6 CFU on Day 1. Isoniazid (300 mg) was administered orally every day from Days 29 through 56. Ipilimumab (3 mg/kg) was administered as a 90-minute IV infusion every 3 weeks (± 3 days) on Days 36, 57, 78, and 99.

Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU)

Patients with an induration \<10 mm in diameter after the baseline PPD reactivity test received BCG (IL, 200 µL volume) at a dose of 0.8 - 3.2 × 10\^6 CFU on Day 1. Isoniazid (300 mg) was administered orally every day from Days 29 through 56. Ipilimumab (3 mg/kg) was administered as a 90-minute IV infusion every 3 weeks (± 3 days) on Days 36, 57, 78, and 99.

Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Australia

Region of Enrollment

PS 0 = Fully active, able to carry on all pre-disease performance without restriction; PS 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; PS 2 = Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours; PS 3 = Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours; PS 4 = Completely disabled; cannot carry on any selfcare; totally confined to bed or chair; PS 5 = Dead

Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) at Baseline

As the study was terminated early due to slow enrollment, immune response (cellular, humoral, in situ) analyses were not performed as outlined in the protocol due to small sample sizes within each arm.

Jonathan Skipper PhD

Any TEAE

Maximum grade 1 TEAE

Maximum grade 2 TEAE

Maximum grade 3 TEAE

Maximum grade 4 TEAE

BCG-related TEAE

Ipilimumab-related TEAE

Isoniazid-related TEAE

Serious TEAE

TEAE Leading to BCG Discontinuation

TEAE Leading to Ipilimumab Discontinuation

TEAE Leading to Isoniazid Discontinuation

TEAE Meeting DLT Criteria

The Safety Analysis Set includes all patients who received at least 1 dose of study treatment.

Number of Patients With Treatment-emergent Adverse Events

Best response: SD

Best response: PD

The Efficacy Analysis Set includes all patients who received at least 1 dose of study treatment and had response evaluated through Week 17.

Number of Patients With Best Overall Clinical Tumor Response

Best response: irSD

Best response: irPD

Not evaluable by irRC

Number of Patients With Best Overall Immune-related Tumor Response

Overall Study

Melanoma, Cutaneous Malignant

852A

Study 1501-852A is a Phase 1 Study with the objective of determining safety and the highest tolerated dose of an immune response modifier cream directly applied to advanced, inoperable, melanoma skin lesions. The study will also measure blood levels of the drug and examine the potential anti-tumor activity of the cream.

Safety and Efficacy of an Immune Response Modifier to Treat Inoperable Advanced Melanoma Skin Lesions

Pfizer

Director, Clinical Trial Disclosure Group

Amino Acids

Pembrolizumab

Antibodies

Immunoglobulins

Tyrosine

Cabozantinib will be administered in the tablet form, at three dose levels: 40, 20 and 60 mg per day. Pembrolizumab will be administered as an intravenous infusion at a fixed dose of 200 mg once every 3 weeks.

Cabozantinib is an oral small molecule potent inhibitor of pro-invasive receptor tyrosine kinases (RTKs).

Cabozantinib will be administered in the tablet form, at three dose levels: 40, 20 and 60 mg per day, in combination with pembrolizumab. The drug is taken continuously for 21 days or 3 weeks. This period of time is defined as one treatment cycle.

Cabozantinib

Pembrolizumab is a humanized antibody which will be administered as an intravenous infusion at a fixed dose of 200 mg once every 3 weeks in combination with cabozantinib.

Yousef Zakharia, MD

Yousef Zakharia

The study aims to evaluate the safety and preliminary efficacy of the combination of cabozantinib and pembrolizumab in advanced melanoma

This is an open-label, Phase 1b/2 trial for adults with advanced melanoma. The objective of the Phase 1b portion of the study is to establish the recommended Phase 2 dose of cabozantinib in combination with pembrolizumab in patients with unresectable melanoma and assess the safety and tolerability of the combined treatments. The objective of the Phase 2 portion of the study is to evaluate the preliminary efficacy of the established dose of cabozantinib in combination with pembrolizumab as measured by best overall response rate (ORR) (complete response \[CR\] + partial response \[PR\]) with the combination of agents in patients with unresectable stage III or stage IV melanoma.

Cabozantinib and Pembrolizumab for Advanced Metastatic Melanoma

Cabozantinib and Pembrolizumab as a Front-line Therapy for Advanced Metastatic Melanoma

All adverse events (AEs )will be considered in DLT assessment unless an event is clearly unrelated to trial treatment. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 will be used.

Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 will be used to determine ORR.

DCR defined as the percentage of patients achieving CR+PR +SD

PFS is defined as the time between the first dose of study therapy and the earliest date of progression or death (participants who have neither progressed nor died will be censored at the most recent last-known-alive date).

OS is defined as defined as the time between the first dose of study therapy and death (participants who have not died will be censored at the most recent last-known-alive date).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of TAK-733 in Adult Patients With Advanced Nonhematologic Malignancies	NCT00948467	Advanced Non-he... Advanced Metast...	TAK-733	18 Years -	Millennium Pharmaceuticals, Inc.
Study of TAK-733 in Adult Patients With Advanced Nonhematologic Malignancies	NCT00948467	Advanced Non-he... Advanced Metast...	TAK-733	18 Years -	Millennium Pharmaceuticals, Inc.
Phase I Study of Intralesional Bacillus Calmette-Guerin (BCG) Followed by Ipilimumab in Advanced Metastatic Melanoma	NCT01838200	Metastatic Mela...	Bacillus Calmet... Ipilimumab Isoniazid	18 Years -	Ludwig Institute for Cancer Research
Safety and Efficacy of an Immune Response Modifier to Treat Inoperable Advanced Melanoma Skin Lesions	NCT00091689	Melanoma	852A	18 Years -	Pfizer
Safety and Efficacy of an Immune Response Modifier to Treat Inoperable Advanced Melanoma Skin Lesions	NCT00091689	Melanoma	852A	18 Years -	Pfizer
Study of TAK-733 in Adult Patients With Advanced Nonhematologic Malignancies	NCT00948467	Advanced Non-he... Advanced Metast...	TAK-733	18 Years -	Millennium Pharmaceuticals, Inc.
Cabozantinib and Pembrolizumab for Advanced Metastatic Melanoma	NCT03957551	Advanced Metast...	Cabozantinib Pembrolizumab	18 Years -	University of Iowa

Spots Global Cancer Trial Database for advanced metastatic melanoma