Neoplasms

All Conditions

Digestive System Diseases

Adenocarcinoma

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Trametinib

Panitumumab

Antineoplastic Agents, Immunological

Immunoglobulins, Intravenous

Immunologic Factors

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients with EGFR ectodomain mutation receive panitumumab IV over 30-90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Cohort 2.

Patients with KRAS, NRAS, or BRAF mutation receive trametinib PO QD on days 1-14 and panitumumab as in Cohort 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Patients without EGFR ectodomain, KRAS, NRAS, or BRAF mutation receive panitumumab as in Cohort 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Cohort 2.

Laboratory Biomarker Analysis

Christine Parseghian

This phase II clinical trial studies how well panitumumab with or without trametinib works in treating patients with stage IV colorectal cancer. Immunotherapy with monoclonal antibodies, such as panitumumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving panitumumab with or without trametinib may work better in treating patients with stage IV colorectal cancer.

PRIMARY OBJECTIVES:

I. To evaluate the anti-tumor efficacy of panitumumab monotherapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently have detectable EGFR ectodomain mutation post-progression in circulating free tumor deoxyribonucleic acid (DNA).

II. To evaluate the anti-tumor efficacy of panitumumab and trametinib combination therapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently have detectable levels of KRAS, NRAS, and/or BRAF mutation post-progression in circulating free tumor DNA.

III. To evaluate the anti-tumor efficacy of panitumumab monotherapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently do not have detectable KRAS, NRAS, BRAF, or EGFR ectodomain mutation post-progression in circulating free tumor DNA.

SECONDARY OBJECTIVES:

I. To evaluate the toxicities of panitumumab and trametinib combination therapy.

II. To evaluate the anti-tumor efficacy of panitumumab and trametinib combination therapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who progressed on prior anti-EGFR therapy, developed detectable EGFR ectodomain mutations, and progress through retreatment with panitumumab.

III. To evaluate the anti-tumor efficacy of panitumumab and trametinib combination therapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who progressed on prior anti-EGFR therapy, did not develop detectable mutations in KRAS, NRAS, BRAF, or EGFR ectodomain, and progress through retreatment with panitumumab.

IV. To evaluate clinical outcomes with panitumumab monotherapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently have detectable EGFR ectodomain mutation post-progression in circulating free tumor DNA.

V. To evaluate clinical outcomes with panitumumab and trametinib combination therapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently have detectable levels of KRAS, NRAS, and/or BRAF mutation post-progression in circulating free tumor DNA.

VI. To evaluate clinical outcomes with panitumumab monotherapy in patients who were initially KRAS/NRAS/BRAF wild-type at baseline who have progressed on prior anti-EGFR therapy and subsequently do not have detectable KRAS, NRAS, BRAF, or EGFR ectodomain mutation post-progression in circulating free tumor DNA.

VII. To study the biological basis of development of primary and secondary resistance to anti-EGFR antibodies and MEK inhibitors.

OUTLINE: Patients are assigned to 1 of 3 cohorts.

COHORT 1: Patients with EGFR ectodomain mutation receive panitumumab intravenously (IV) over 30-90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Cohort 2.

COHORT 2: Patients with KRAS, NRAS, or BRAF mutation receive trametinib orally (PO) once daily (QD) on days 1-14 and panitumumab as in Cohort 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

COHORT 3: Patients without EGFR ectodomain, KRAS, NRAS, or BRAF mutation receive panitumumab as in Cohort 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Cohort 2.

After completion of study treatment, patients are followed up for 4 weeks and then every 3 months for 24 months.

Panitumumab With or Without Trametinib in Treating Patients With Stage IV Colorectal Cancer

A Phase II Enrichment Study of Panitumumab as a Single Agent or in Combination With Trametinib in Anti-EGFR-Refractory Stage IV Colorectal Cancer Patients

Will be evaluated along with the exact 95% confidence interval.

The incidence rates will be estimated, along with the exact 95% confidence intervals.

The probability of PFS will be estimated using the method of Kaplan and Meier. The two-sided log-rank test will be used to assess the differences between groups.

The probability of OS will be estimated using the method of Kaplan and Meier. The two-sided log-rank test will be used to assess the differences between groups.

National Cancer Institute (NCI)

M.D. Anderson Cancer Center

60 mg once daily. Route: per os Cycle: 28 days

cabozantinib in patients with refractory mCRC

Cabozantinib

Erika Martinelli, MD, PhD

This is a phase II non-randomised and non-comparative study, in pretreated mCRC patients, progressed after at least 2 lines of prior chemotherapy for metastatic disease.

Treatment plan:

* First Stage: A total of 22 patients will be enrolled in the first stage to detect at least 3 patients free of progression at 16 weeks
* Second Stage: If at least 3 patients will be free of progression at 16 weeks, an additional cohort of 11 patients will be enrolled in the second stage

The prognosis of patients diagnosed with metastatic colorectal cancer (mCRC) remains poor despite significant progress made in the treatment efficacy and tolerability. The introduction of cytotoxic drugs (i.e. oxaliplatin, irinotecan, and trifluridine/tipiracil) and molecular targeted agents (i.e. bevacizumab, cetuximab, panitumumab, aflibercept, and regorafenib), has dramatically improved patients outcomes with an increase in median overall survival from 6 months with best supportive care only, to more than 30 months with new treatment strategies. The recent advances in genomic technologies have provided further insight into the profound complexity and molecular heterogeneity of colorectal cancer. According to the recent Consensus on CRC Molecular Subtypes (CMS) four biologically distinct subtypes have been identified.

CMS1 (14%) occurring more often in older age, female patients, is characterized by right-sided tumors, hypermutated, enriched for MSI and BRAF mutant and with immune pathway activation. CMS2 (37%) shows epithelial phenotype, left-sided location, chromosomal instability (CIN), microsatellites stable (MSS), TP53 mutation, WNT/MYC pathway activation, and Epidermal Growth Factor Receptor (EGFR) upregulation and is associated with better survival rates; CMS3(13%), also expressing epithelial phenotype, is highly heterogeneous in CIN/MSI status and KRAS and PIK3CA mutant; CMS4 (23%) is defined by mesenchymal phenotype, increased TGF-β and AXL signalling, younger age at diagnosis, invasive phenotype, NOTCH3/VEGFR2 overexpression, and worse survival outcomes. This knowledge cannot be immediately translated into clinical practice, since CMS is not yet used to stratify patients for anti-cancer treatment. However, a better understanding of the complex molecular landscape in CRC will contribute to new treatment strategies.

Cabozantinib is an oral, small-molecule inhibitor of tyrosine kinases, including MET, VEGF receptor 2 (VEGFR2), AXL and RET, currently approved for the treatment of patients with progressive, metastatic medullary thyroid cancer; treatment-naïve patients with renal cell carcinoma with intermediate or poor risk disease or previously treated with a vascular endothelial growth factor (VEGF)-inhibitor; hepatocellular carcinoma (HCC) previously treated with sorafenib.

Angiogenesis is a crucial mechanism in CRC development and progression Moreover, AXL and MET signalling pathways are implicated in CRC invasion and metastasis and are involved in drug resistance occurrence .

Cabozantinib has shown antitumor activity in preclinical CRC patient-derived tumor xenograft (PDTX) model leading to a decrease in the phosphorylation of Tie2, VEGFR2 (pro-angiogenic factors) and the MET, RET and AXL receptors (oncogenic pathways).

caBozantinib in Pre-treated pAtients With Metastatic COlorectal Cancer.

A Phase II Trial Evaluating the Activity of caBozantinib in Pre-treated pAtients With Metastatic COlorectal Cancer (mCRC). ABACO Trial.

Progression Free Survival (PFS) rate at 16 weeks: the rate of patients who have not experienced disease progression or death for any cause at 16 weeks.

calculated from the start of the study treatment until disease progression or death for any cause.

calculated from the start of the study treatment until death for any cause.

rate of patients with complete response or partial response, as best response.

rate of patients with complete response, partial response and stable disease, as best response.

Adverse events graded according Criteria for Adverse Events (CTCAE) Version(v.) 5.0.

University of Campania "Luigi Vanvitelli"

Professor

Anti-Infective Agents

Pembrolizumab

poly(I).poly(c12,U)

Immune Checkpoint Inhibitors

Antiviral Agents

Patients receive rintatolimod IV over 30 minutes on days 1-3 and pembrolizumab IV over 30 minutes on day 3. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 4, patients receive rintatolimod IV over 30 minutes and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 24 months from the first dose in the absence of disease progression or unacceptable toxicity.

Questionnaire Administration

Rintatolimod

Christos Fountzilas, MD

This phase IIa trial studies how well rintatolimod and pembrolizumab works in treating patients with colorectal cancer that does not respond to treatment (refractory), has spread to other places in the body (metastatic), or otherwise cannot be removed by surgery (unresectable). Rintatolimod is an immuno-oncology agent that can stimulate the immune system. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving rintatolimod and pembrolizumab together may work better than standard of care in treating patients with colorectal cancer.

PRIMARY OBJECTIVE:

I. Determine the objective response rate of patients with metastatic colorectal cancer (mCRC) treated with rintatolimod + pembrolizumab.

SECONDARY OBJECTIVES:

I. Establish the adverse event profile of combining rintatolimod and pembrolizumab.

II. Estimate the median progression free survival and overall survival of patients with mCRC treated with rintatolimod and pembrolizumab.

III. Determine the immune objective response rate of patients with mCRC treated with rintatolimod + pembrolizumab.

EXPLORATORY OBJECTIVES:

I. Assess modulation of the levels of CD8alpha expression and cytotoxic T-lymphocyte (CTL) density pre- and post-therapy.

II. Assess chemokine levels in the tumor microenvironment and peripheral blood, including effector T cell (Teff)-attracting and regulatory T cell (Treg)-favoring chemokines.

III. Characterize the fecal microbiotic profile and correlate those results with antitumor immune responses.

OUTLINE:

Patients receive rintatolimod intravenously (IV) over 30 minutes on days 1-3 and pembrolizumab IV over 30 minutes on day 3. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 4, patients receive rintatolimod IV over 30 minutes and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 24 months from the first dose in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 and 90 days, and every 6 months for up to 2 years.

Rintatolimod and Pembrolizumab for the Treatment of Refractory Metastatic or Unresectable Colorectal Cancer

A Phase IIa Study of Rintatolimod Plus Pembrolizumab in Refractory Metastatic Colorectal Cancer

Determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and estimated using a 90% confidence interval obtained using Jeffrey?s prior method.

Toxicities and adverse events (according to Common Terminology Criteria in Adverse Events \[CTCAE\] version 5.0) will be summarized by attribution and grade using frequencies and relative frequencies.

Will be summarized using standard Kaplan-Meier methods; where estimates of median survival and 6/12-month survival rates will be obtained with 95% confidence intervals.

Determined by immune-modified (i)RECIST and estimated using a 90% confidence interval obtained using Jeffrey?s prior method.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Panitumumab With or Without Trametinib in Treating Patients With Stage IV Colorectal Cancer	NCT03087071	EGFR NP_005219.... KRAS Gene Mutat... MAP2K1 Gene Mut... Metastatic Colo... Refractory Colo... Stage IV Colore... Stage IVA Color... Stage IVB Color...	Laboratory Biom... Panitumumab Trametinib	18 Years -	M.D. Anderson Cancer Center
caBozantinib in Pre-treated pAtients With Metastatic COlorectal Cancer.	NCT06171854	Refractory Colo...	Cabozantinib	18 Years -	University of Campania "Luigi Vanvitelli"
Panitumumab With or Without Trametinib in Treating Patients With Stage IV Colorectal Cancer	NCT03087071	EGFR NP_005219.... KRAS Gene Mutat... MAP2K1 Gene Mut... Metastatic Colo... Refractory Colo... Stage IV Colore... Stage IVA Color... Stage IVB Color...	Laboratory Biom... Panitumumab Trametinib	18 Years -	M.D. Anderson Cancer Center
Rintatolimod and Pembrolizumab for the Treatment of Refractory Metastatic or Unresectable Colorectal Cancer	NCT04119830	Metastatic Colo... Microsatellite ... Mismatch Repair... Refractory Colo... Stage III Color... Stage IIIA Colo... Stage IIIB Colo... Stage IIIC Colo... Stage IV Colore... Stage IVA Color... Stage IVB Color... Stage IVC Color... Unresectable Co...	Pembrolizumab Questionnaire A... Rintatolimod	18 Years -	Roswell Park Cancer Institute

Spots Global Cancer Trial Database for refractory colorectal adenocarcinoma