Neoplasms

All Conditions

Digestive System Diseases

Adenocarcinoma

Colorectal Neoplasms

Colonic 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

Anti-Inflammatory Agents

All Drugs and Chemicals

Clobetasol

Glucocorticoids

Hormones

Hormone Antagonists

Patients receive lower-dose regorafenib PO QD on days 1-21 and pre-emptive clobetasol propionate given topically BID for 12 weeks, beginning on day 1 of regorafenib.

Patients receive lower-dose regorafenib PO as in Arm A1 and reactive clobetasol propionate given topically BID beginning on day 1 per physician discretion upon occurrence of PPES grade \>= 1.

Patients receive standard dose regorafenib PO QD on days 1-21 and pre-emptive clobetasol propionate as in Arm A1.

Patients receive standard dose regorafenib PO as in Arm B1 and reactive clobetasol propionate as in Arm A2.

Clobetasol Propionate

Pharmacological Study

Quality-of-Life Assessment

Regorafenib

Tanios Bekaii-Saab

This randomized phase II trial studies how well lower-dose compared to standard dose regorafenib works in treating patients with colorectal cancer that has spread from the primary site (place where it started) to other places in the body and does not respond to treatment. Regorafenib may stop the growth of colorectal cancer by blocking the growth of new blood vessels necessary for tumor growth and by blocking some of the enzymes needed for cell growth. It is not yet known whether lower-dose or standard dose regorafenib is more effective in treating patients with colorectal cancer. Clobetasol propionate is a steroid cream that is commonly used to treat a variety of skin conditions and may help prevent hand-foot skin reactions in patients receiving regorafenib.

PRIMARY OBJECTIVES:

I. Evaluate the proportion of patients who complete 2 cycles of protocol treatment and initiate cycle 3 in arm A (pooled arm A1 and A2) and arm B (pooled arm B1 and B2).

SECONDARY OBJECTIVES:

I. Evaluate outcome measures for efficacy in each arm including progression-free survival (PFS), time to progression (TTP), and overall survival (OS).

II. Compare between arms the cumulative dose and dose intensity received within the first two cycles.

III. Evaluate the proportion of patients in each arm that exhibit grade 3 palmar-plantar erythrodysesthesia syndrome (PPES) and/or fatigue, and make comparisons between regorafenib dosing strategies and pre-emptive versus (vs.) reactive strategies to address PPES.

IV. Compare quality of life (QOL) between treatment arms (regorafenib dosing strategies and preemptive vs. reactive PPES strategies) as measured by the Hand and Foot Syndrome (HFS)14, Brief Fatigue Inventory (BFI), and Linear Analogue Self-Assessment (LASA) questionnaires.

TERTIARY OBJECTIVES:

I. Evaluate and compare trough minimum concentration (Cmin) pharmacokinetics (PK) during the first 2 treatment cycles for regorafenib and active metabolites M2, M5 between the low dose (dose escalation) and the standard dose cohorts, and correlate with toxicity profile.

II. Evaluate the correlation between PK parameters and tumor response/stable disease after the first two cycles.

III. Evaluate the correlation between PK parameters and PFS and OS. IV. Evaluate if trough (Cmin) concentrations are associated with patient-specific factors (such as ? but not limited to ? age and concomitant medications).

OUTLINE: Patients are randomized to 1 of 4 treatment arms.

ARM A1: Patients receive lower-dose regorafenib PO once daily (QD) on days 1-21 and pre-emptive clobetasol propionate given topically twice daily (BID) for 12 weeks, beginning on day 1 of regorafenib.

ARM A2: Patients receive lower-dose regorafenib PO as in Arm A1 and reactive clobetasol propionate given topically BID beginning on day 1 per physician discretion upon occurrence of PPES grade \>= 1.

ARM B1: Patients receive standard dose regorafenib PO QD on days 1-21 and pre-emptive clobetasol propionate as in Arm A1.

ARM B2: Patients receive standard dose regorafenib PO as in Arm B1 and reactive clobetasol propionate as in Arm A2.

In all arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 2-6 months.

Lower or Standard Dose Regorafenib in Treating Patients With Refractory Metastatic Colorectal Cancer

Regorafenib Dose Optimization Study (ReDOS): A Phase II Randomized Study of Lower Dose Regorafenib Compared to Standard Dose Regorafenib in Patients With Refractory Metastatic Colorectal Cancer (mCRC)

After quantitation, the average trough concentration, calculated from all available data, will be calculated. This average trough concentration will be correlated with toxicity and efficacy endpoints. Further descriptive characteristics of the pharmacokinetics will also be calculated, an example includes (but is not limited to) within-patient variability in the trough concentrations pharmacokinetic parameters will also be calculated, both overall and within courses, as a ratio of the maximum:minimum value.

Fisher exact test will be used to detect a difference course 3 between arms (starting low dose \[pooled arm A1 and A2\] versus \[vs.\] standard dose \[pooled arm B1 and B2\]). The proportion of patients who complete 2 courses of protocol treatment and initiate course 3 will be computed by arm with its 95% confidence interval using exact method.

OS is defined as the time from randomization to death due to any cause and will be estimated with Kaplan-Meier survival curves and differences between regorafenib arms (A vs. B) tested using log-rank tests, though these analyses are not powered for formal non-inferiority assessments.

PFS is defined as the time from randomization to the earlier of disease progression or death due to any cause, where progressed disease (PD) is defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and will be estimated with Kaplan-Meier survival curves and differences between regorafenib arms (A vs. B) tested using log-rank tests, though these analyses are not powered for formal non-inferiority assessments.

TTP is defined as the time from randomization to disease progression, where PD is defined by RECIST 1.1 and will be estimated with Kaplan-Meier survival curves and differences between regorafenib arms (A vs. B) tested using log-rank tests, though these analyses are not powered for formal non-inferiority assessments.

Will be summarized with descriptive statistics and compared between regorafenib arms (A vs. B).

Dose intensity of regorafenib received by patients in the first two cycles as measured by the percentage (%) of planned dose received

Will be computed with 95% confidence intervals, and differences between regorafenib dosing strategies (pooled across HFS strategies) tested using a Fisher Exact test. The incidence of grade 3 or 4 HFS will also be descriptively compared between those receiving a pre-specified preemptive vs. reactive approach for hand and foot syndrome (pooled across dosing strategies), and tested using a Fisher Exact test.

Patients will be descriptively compared between treatment arms and between HFS treatment strategies (pre-emptive vs. reactive) according to self-reported outcomes given on the HFS14 questionnaire. Results from the course 1 and 2 HSF14 questionnaires will also be summarized descriptively as they relate to the pre-emptive versus reactive palmar-plantar erythrodysesthesia syndrome (PPES) strategies, with comparisons made within and between arms using the t-test or Wilcoxon rank sum test as appropriate, as well as taking time-dependence into account.

Changes in QOL (according to the LASA questionnaire as measured by the overall QOL question) from baseline will be compared between the treatment arms using the Kruskal-Wallis test.

National Cancer Institute (NCI)

Academic and Community Cancer Research United

Each CTCAE term is a representation of a specific event used for medical documentation \& analysis \& is a single MedDRA Lowest Level Term (LLT). All graded AEs are reported for non-cancel patients. Serious AE (SAE) reports may include any secondary serious or non-serious events considered related to the primary event (the reason for filing an expedited report); collectively, these events are referred to as Expedited AEs, \& appear in the SAE table.

In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy).

Arm A1 (Regorafenib Dose Escalation + Pre-emptive Strategy)

In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy).

Arm A2 (Regorafenib Dose Escalation + Reactive Strategy)

In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy).

Arm B1 (Regorafenib Standard Dose + Pre-emptive Strategy)

In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials. Patients also had the clobetasol cream applied when HFSR developed (reactive strategy).

Arm B2 (Regorafenib Standard Dose + Reactive Strategy)

In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy).

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Eastern Cooperative Oncology Group PS Scale: 0)Fully active, able to carry on all pre-disease performance without restriction; 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; 2)Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3)Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4)Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.

ECOG Performance Status

The data for the pre-emptive and reactive treatment with clobatasol were pooled for the comparison of the two dosing strategies (regorafenib dose escalation group (Arms A1 + A2) versus regorafenib standard dose group (Arms B1 + B2)).

Tanios Bekaii-Saab, M.D.

In the regorafenib dose escalation group, the starting dose of regorafenib was 80 mg/day in week 1, 120 mg/day in week 2, and 160 mg/day in week 3 for cycle 1. Weekly incremental dose-escalation occurred if no significant drug-related toxicities (SDRTs) were observed. In cycle 2, patients received the highest tolerated dose from cycle 1. Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy).

Regorafenib Dose Escalation Group

In the regorafenib standard dose group, the regorafenib dose schedule of 160 mg/day started on day 1 and continued for 21 every 28 days. The dose of 160 mg as the standard dose was used since it is the approved and most commonly used dose/schedule in clinical practice based on the results of randomized trials.Patients also received prophylactic 0.05% clobetasol cream twice daily applied to palms and soles starting at cycle 1 day 1 for prevention of HFSR (pre-emptive strategy) or had the clobetasol cream applied when HFSR developed (reactive strategy).

Regorafenib Standard Dose Group

Proportion of Patients in Each Arm Who Complete 2 Cycles of Protocol Treatment and Initiate Cycle 3

Overall Survival (OS)

Progression Free Survival (PFS)

Time to Progression (TTP)

Cycle 1

Cycle 2

The data for the pre-emptive \& reactive treatment with clobatasol were pooled for the comparison of the two dosing strategies ((Arms A1 + A2) versus (Arms B1 + B2)). There are patients off-protocol treatment during cycle 1; therefore, we do not have cycle 2 dosing information for those patients who are off-protocol treatment during cycle 1.

Cumulative (Total) Dose of Regorafenib Received by Patients in the First Two Cycles

The data for the pre-emptive \& reactive treatment with clobatasol were pooled for the comparison of the two dosing strategies ((Arms A1 + A2) versus (Arms B1 + B2)).

Dose Intensity of Regorafenib Received by Patients in the First Two Cycles as Measured by the Percentage of Planned Dose Received

Proportion of Patients Overall and Within Each Arm Experiencing Grade 3 or 4 Hand and Foot Syndrome (HFS) or Fatigue

Changes in Quality of Life (QOL) (According to the HFS14 Questionnaire)

Changes in QOL (According to the Linear Analogue Self-Assessment [LASA] Questionnaire)

Pharmacokinetics (PK) Parameters of Regorafenib Using Liquid Chromatography Mass Spectrometry

Overall Study

Antineoplastic Agents

Micronutrients

Hematinics

Bone Density Conservation Agents

Vitamins

Amino Acids

Oxaliplatin

Leucovorin

Fluorouracil

Antibodies

Antibodies, Monoclonal

Capecitabine

Levoleucovorin

Calcium

Folic Acid

Immunoglobulins

Calcium, Dietary

Panitumumab

Tetrahydrofolates

Formyltetrahydrofolates

Vitamin B Complex

Antineoplastic Agents, Immunological

Immunoglobulins, Intravenous

Immunologic Factors

Antimetabolites

Immunosuppressive Agents

Antidotes

Protective Agents

Trace Elements

Folinic Acid

Folate

Vitamin B9

Glutamic Acid

INDUCTION Patients receive panitumumab IV over 30-60 minutes, oxaliplatin IV over 2 hours, leucovorin calcium IV, and fluorouracil over 46-48 hours on day 1. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE:

Patients receive panitumumab IV over 30 minutes, leucovorin calcium IV, and fluorouracil over 46-48 hours on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

INDUCTION Patients receive panitumumab IV over 30-60 minutes, oxaliplatin IV over 2 hours, leucovorin calcium IV, and fluorouracil over 46-48 hours on day 1. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE:

Patients receive capecitabine PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Leucovorin Calcium

Laboratory Biomarker Analysis

Afsaneh Barzi, MD

This randomized trial studies how well panitumumab, leucovorin calcium, and fluorouracil after combination chemotherapy and panitumumab induction work in treating patients with RAS wild type colorectal cancer that has spread from where it started to nearby tissue or lymph nodes or other places in the body or cannot be removed by surgery. Monoclonal antibodies, such as panitumumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving panitumumab, leucovorin calcium, and fluorouracil after combination chemotherapy and panitumumab induction may work better in treating patients with colorectal cancer.

PRIMARY OBJECTIVES:

I. To compare the duration of progression free survival 1 (PFS1) in patients with RAS wild type who have received induction leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX) + panitumumab and not progressed at 6 cycles and randomized to maintenance therapy with fluorouracil (5FU) based therapy with or without panitumumab.

SECONDARY OBJECTIVES:

I. To compare the response rate (RR) in patients with RAS wild type who are randomized to maintenance therapy with 5FU based therapy to those randomized to 5FU based therapy with panitumumab.

TERTIARY OBJECTIVES:

I. Progress free survival 2 (PFS2). II. To assess the adverse event (AE) profile and safety of the proposed treatment in this population.

III. To assess and compare the overall survival (OS) between the two treatment groups.

IV. To compare the quality of life (QOL) as measured by health state index (HIS) between patients who achieve partial response (PR) versus (vs.) those who progress and those who have stable disease during the induction phase.

V. To compare the QOL as measured by HSI between the two groups randomized to maintenance therapy.

VI. To assess the evolution of RAS mutation under treatment during induction phase as well as maintenance.

VII. To explore relationship between genomic and proteomic alterations of the tumor with response and PFS to panitumumab.

OUTLINE:

INDUCTION:

Patients receive panitumumab intravenously (IV) over 30-60 minutes, oxaliplatin IV over 2 hours, leucovorin calcium IV, and fluorouracil over 46-48 hours on day 1. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients who are not candidates for surgery, have no disease progression, or do not have complete response after Induction are randomized to 1 of 2 arms.

ARM I: Patients receive panitumumab IV over 30 minutes, leucovorin calcium IV, and fluorouracil over 46-48 hours on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive capecitabine orally (PO) twice daily (BID) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

5-FU Based Maintenance Therapy in RAS Wild Type Metastatic Colorectal Cancer After Induction With FOLFOX Plus Panitumumab

Randomized Phase III Trial of 5-FU Based Maintenance Therapy With or Without Panitumumab in Patients With RAS Wild Type Metastatic Colorectal Cancer After Induction With FOLFOX + Panitumumab

Disease progression will be determined by comparing tumor measurement during maintenance therapy to baseline measurement before starting maintenance treatment using Response Evaluation Criteria in Solid Tumors 1.1. will be conducted based on the intent-to-treat population from the time of randomization.

Response will be evaluated using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Lower or Standard Dose Regorafenib in Treating Patients With Refractory Metastatic Colorectal Cancer	NCT02368886	Colon Adenocarc... Rectal Adenocar... Stage III Color... Stage IIIA Colo... Stage IIIB Colo... Stage IIIC Colo... Stage IV Colore... Stage IVA Color... Stage IVB Color...	Clobetasol Prop... Pharmacological... Quality-of-Life... Regorafenib	18 Years -	Academic and Community Cancer Research United
5-FU Based Maintenance Therapy in RAS Wild Type Metastatic Colorectal Cancer After Induction With FOLFOX Plus Panitumumab	NCT03300609	Colorectal Aden... RAS Wild Type Stage III Color... Stage IIIA Colo... Stage IIIB Colo... Stage IIIC Colo... Stage IV Colore... Stage IVA Color... Stage IVB Color...	Panitumumab Oxaliplatin Leucovorin Calc... Fluorouracil Capecitabine Quality-of-Life... Laboratory Biom...	18 Years -	University of Southern California
Lower or Standard Dose Regorafenib in Treating Patients With Refractory Metastatic Colorectal Cancer	NCT02368886	Colon Adenocarc... Rectal Adenocar... Stage III Color... Stage IIIA Colo... Stage IIIB Colo... Stage IIIC Colo... Stage IV Colore... Stage IVA Color... Stage IVB Color...	Clobetasol Prop... Pharmacological... Quality-of-Life... Regorafenib	18 Years -	Academic and Community Cancer Research United

Spots Global Cancer Trial Database for stage iiia colorectal cancer ajcc v7