Neoplasms

Digestive System Diseases

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Colonic Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

All Drugs and Chemicals

Antineoplastic Agents

Herbal and Botanical

Antibodies

Cetuximab

Immunoglobulins

Antineoplastic Agents, Immunological

Cola

AZD6244 once daily on days 1, 8, 15 and 22. Cetuximab 400 mg/m2 IV loading dose over 120minutes on day 1 and cetuximab 250 mg/m2 IV loading dose over 60 minutes on days 8, 15,22

AZD6244 twice daily on days 1, 8, 15 and 22. Cetuximab 400 mg/m2 IV loading dose over 120minutes on day 1 and cetuximab 250 mg/m2 IV loading dose over 60 minutes on days 8, 15,22

Day 1 administer cetuximab 400 mg/m2 IV loading dose over 120 minutes. On days 8, 15 and 22 administer cetuximab 250 mg/m2 IV loading dose over 60 minutes

Given orally once or twice a day depending on dose level.On days 1, 8, 15 and 22. Repeat every 28 days

AZD6244

Austin G Duffy, M.D.

Background:

- The experimental cancer treatment drug AZD6244 has been shown to block signals that tell cancer cells to grow. Cetuximab, a drug approved to treat cancer of the head, neck, colon, and rectum, also blocks signals that tell cancer cells to grow. Researchers are investigating the highest safe dose of AZD6244 to give with cetuximab, and will also investigate the effectiveness of this drug combination in individuals who have colorectal cancer that involves a particular protein known as the K-RAS protein. Cetuximab is not used to treat colorectal cancer with K-RAS tumors because it has not been shown to be effective, but researchers believe that adding AZD6244 to cetuximab may improve how well cetuximab works, even in people with K-RAS tumors.

Objectives:

* To evaluate the safety and effectiveness of AZD6244 in combination with cetuximab for solid tumors that have not responded to standard treatment.
* To evaluate the safety and effectiveness of AZD6244 in combination with cetuximab for colorectal cancer that involves the K-RAS protein and has not responded to standard treatment.

Eligibility:

* Individuals at least 18 years of age who have been diagnosed with solid tumors that have not responded to standard treatment.
* Individuals at least 18 years of age who have been diagnosed with colorectal cancer that has not responded to standard treatment.

Design:

* This protocol will involve two separate studies: an initial study to establish the highest safe and effective dose of AZD6244 and cetuximab in individuals with solid tumors, and an expansion study of AZD6244 and cetuximab in individuals with colorectal cancer involving the K-RAS protein.
* Participants will be screened with a full medical history and physical examination, blood samples, imaging studies, and other tests as required by the researchers.
* AZD6244 is a capsule to be swallowed once or twice a day, every day, with water on an empty stomach. Cetuximab will be given intravenously once a week, over 2 hours for the first dose and over an hour for every following dose. This combination of daily AZD6244 and weekly cetuximab will be repeated in 28-day cycles of treatment. Participants will keep a diary to record the time of taking AZD6244 each day, as well as any side effects.
* Participants will have frequent blood tests and other exams during the first cycle of treatment, up to five visits to the National Institutes of Health (NIH) and other visits to their local doctor to in the first 28-day cycle.
* During subsequent cycles, participants will have four visits to NIH and four visits to your local doctor for examinations, blood tests, and imaging studies.
* Participants may continue to receive the AZD6244 with cetuximab for up to 6 cycles, until the tumor grows, unacceptable side effects development, or the participant or participant's doctor decides to stop participation. There will be a final study visit that repeats the procedures performed during the screening visit....

Background:

* AZD6244 is an oral highly selective and potent uncompetitive inhibitor of mitogen-activated protein kinase 1/2 (MEK1/2).
* The presence of KRAS mutations predict resistance to EGFR-directed antibody therapy of metastatic colorectal cancer. This appears secondary to KRAS activation of signaling cascades downstream of the EGFR receptor, including the RAF/MEK/ERK pathway.
* Our hypothesis is that EGFR inhibition by cetuximab would be augmented in patients with KRAS mutations if activation of the RAF/MEK/ERK cascade were to be inhibited.

Objectives:

* To determine the dose limiting toxicities and the maximum tolerated dose of AZD6244 in combination with cetuximab in advanced, refractory solid tumors.
* To assess for evidence of anti-tumor activity with this combination, per tumor measurements using RECIST criteria.
* To evaluate the pharmacokinetics of AZD6244 and cetuximab when administered concomitantly.
* To evaluate the safety and tolerability of the combination of AZD6244 and cetuximab in patients with K-RAS mutated metastatic colorectal cancer.
* To assess the inhibition of the RAF/MEK/ERK pathway in peripheral blood mononuclear cells secondary to treatment with AZD6244.
* To evaluate the pharmacokinetics of AZD6244 in combination with cetuximab and the relation to treatment side effects.

Eligibility:

* Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective. In the MTD expansion cohort: Patients must have biopsy proven K-RAS mutant, metastatic colorectal cancer.
* Age greater than or equal to 18
* ECOG performance status less than or equal to 2

Study Design:

* This is a phase 1 dose escalation study of AZD6244 in combination with fixed-dose cetuximab with an expanded cohort in K-RAS mutated metastatic colorectal cancer.
* Patients will be treated with AZD6244 orally twice daily continuously, and cetuximab will be administered at standard doses on days 1, 8, 15 and 22. Dose escalations are outlined per the schema in the parent protocol.
* The dose of AZD6244 will be escalated using a 3-patient cohort design based on first cycle toxicities until dose limiting toxicities (DLT) and maximum tolerated dose (MTD) are defined. Once the MTD/RP2D has been identified, an additional 12 patients with K-RAS mutant colorectal cancer will be enrolled at that dose level, in an effort to more fully characterize pharmacokinetic characteristics of this combination. If at least an 8% response rate is observed in the expanded cohort, the combination will be recommended for future analysis.

AZD6244 With Cetuximab for Solid Tumors and Colorectal Cancer

A Phase 1 Study of AZD6244 in Combination With Cetuximab in Refractory Solid Tumors

National Cancer Institute (NCI)

Symptoms and General Pathology

Skin and Connective Tissue Diseases

Rare Diseases

Neoplasm Metastasis

Gastrointestinal Stromal Tumors

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Tin Fluorides

Sunitinib

Growth Inhibitors

Angiogenesis Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Participants will receive both CGT9486 and sunitinib orally until study stopping rules are met.

CGT9486 plus sunitinib

Participants will receive CGT9486 until steady state then both CGT9486 and sunitinib orally until study stopping rules are met.

CGT9486

Participants will receive sunitinib until steady state then both sunitinib and CGT9486 orally until study stopping rules are met.

Participants will receive sunitinib orally until study stopping rules are met.

Cogent Biosciences

Jessica Sachs, MD

This is a Phase 3, open-label, international, multicenter study of CGT9486 in combination with sunitinib. This is a multi-part study that will enroll approximately 426 patients. Part 1 consists of two evaluations: 1) confirming the dose of an updated formulation of CGT9486 to be used in subsequent parts in approximately 20 patients who have received at least one prior line of therapy for GIST and 2) evaluating for drug-drug interactions between CGT9486 and sunitinib in approximately 18 patients who have received at least two prior tyrosine kinase inhibitors (TKIs) for GISTs. The second part of the study will enroll approximately 388 patients who are intolerant to, or who failed prior treatment with imatinib only and will compare the efficacy of CGT9486 plus sunitinib to sunitinib alone with patients being randomized in a 1:1 manner.

This is a multi-part study: Part 1a is a single-arm design, Part 1b is a two-arm parallel design drug-drug interaction evaluation in the first treatment cycle and single-arm design in subsequent treatment cycles, and Part 2 is a randomized two-arm parallel comparator study

(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors

A Phase 3 Randomized, Open-Label, Multicenter Clinical Study of CGT9486+Sunitinib vs. Sunitinib in Subjects With Locally Advanced, Unresectable, or Metastatic Gastrointestinal Stromal Tumors

Area under the plasma concentration-time curve (AUC)

Time to maximum observed plasma concentration (Tmax)

Time from first dose to documented disease progression or death due to any cause, whichever occurs first

Incidence and severity of Adverse Events from first dose of study drug

Incidence and severity of Serious Adverse Events from first dose of study drug

Incidence of Adverse Events leading to dose modifications from first dose of study drug

Change from baseline in laboratory results

Time from first dose to death due to any cause

Percentage of subjects who achieved documented complete response (CR) + confirmed partial response (PR) based on modified Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Percentage of subjects who achieved CR + PR + stable disease (SD) at 16 weeks

Time from first dose to first documented response based on modified Response Evaluation Criteria in Solid Tumors Version 1.1

Time from first response (CR or PR) to the date of progression or death from any cause, whichever occurs first

Change in individual scores in patients with locally advanced, unresectable, or metastatic GIST treated with CGT9486 in combination with sunitinib compared with patients treated with sunitinib monotherapy. The scale comprises 30 questions, 24 of which are aggregated into 9 multi-item scales, to include 5 functioning scales (physical, role, cognitive, emotional and social), 3 symptom scales (fatigue, pain and nausea/vomiting) and 1 global health status scale. The remaining 6 single-item scales assess symptoms (dyspnea, appetite loss, sleep disturbance, constipation, diarrhea and the financial impact). All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status denote a better level of functioning, while higher scores on the symptom and single-item scales indicate a higher level of symptoms.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
AZD6244 With Cetuximab for Solid Tumors and Colorectal Cancer	NCT01287130	Colonic Neoplas... Cancer of the C... Colon Cancer Colon Neoplasms Colonic Cancer	Cetuximab AZD6244	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)
(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors	NCT05208047	Advanced Gastro... Metastatic Canc...	CGT9486 plus su... CGT9486 Sunitinib Sunitinib	18 Years -	Cogent Biosciences, Inc.

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