Skin and Connective Tissue Diseases

All Conditions

Neoplasms

Digestive System Diseases

Exanthema

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

All Drugs and Chemicals

Antineoplastic Agents

Anti-Infective Agents

Antibodies

Cetuximab

Doxycycline

Immunoglobulins

Panitumumab

Patients with metastatic colorectal cancer, qualified to either cetuximab or panitumumab based systemic treatment (either monotherapy or with chemotherapy) receiving a 100 mg of doxycycline daily

Lucjan S Wyrwicz, MD, PhD

Zbigniew I Nowecki, MD, PhD

Lucjan S. Wyrwicz, MD, PhD

Agnieszka Byszek, MPharm

Lucjan S Wyrwicz, MD,PhD

Up to 60% of patients with metastatic colorectal cancer can be treated with one of monoclonal antibodies targeted against epidermal growth factor receptor (EGFR). This treatment is associated with a specific spectrum of toxicity: acne-like rash from limited up to erythema, often with severe pruritus, sometimes combined with other types of skin toxicities (hair and nail changes). Previously in STEPP study investigators shown that pre-emptive treatment with oral doxycycline (200 mg daily), topical steroids and sun blockers reduces the number of more severe skin side effects of panitumumab.

The study is designed to described the profile of skin toxicity of EGFR blocking drugs combined with low-dose doxycycline (100 mg daily) used in the pre-emptive manner.

Patients with metastatic colorectal cancer treated with cetuximab or panitumumab usually develop the skin toxicity which can impair patients' quality of life as well as limit the treatment. We designed this trial to assess the effect of simplified protocol of pre-emptive treatment on the observed skin toxicities during cetuximab and panitumumab treatment of colorectal cancer.

The study is a cohort observational, single center study which should result in estimation of particular types of toxicities, especially occurence of more severe (grade 2 and 3) side effects and assess the tolerance of doxycyline in the prolonged administration.

The observation in the study is biweekly and is continued up to 8 weeks.

Pre-emptive Low-dose Doxycycline During Anti-EGFR Treatment

Prospective Phase II Study on Skin Toxicity on Low-Dose Doxycycline in Metastatic Colorectal Cancer Patients During Cetuximab and Panitumumab Treatment

analyzed for weeks: 2, 4, 6 and 8 separetly

assessed as a correlation to severeness of skin toxicities

Maria Sklodowska-Curie National Research Institute of Oncology

Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology

Colonic Neoplasms

Skin Diseases

Anti-Inflammatory Agents

Micronutrients

Dermatologic Agents

Herbal and Botanical

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Irinotecan

Amoxicillin

Leucovorin

Fluorouracil

Ciprofloxacin

Clavulanic Acid

Anti-Bacterial Agents

Clindamycin

Clindamycin palmitate

Clindamycin phosphate

Histamine Antagonists

Histamine H1 Antagonists

Cefadroxil

Antibiotics, Antitubercular

Sunscreening Agents

Petrolatum

Clavulanic Acids

Emollients

Hydroxyzine

Sulfadiazine

Silver Sulfadiazine

Topoisomerase I Inhibitors

Enzyme Inhibitors

Antineoplastic Agents, Immunological

Cola

Participants received either FOLFIRI and panitumumab 6 mg/kg once every 2 weeks (Q2W) or irinotecan and panitumumab 9 mg/kg once every 3 weeks (Q3W), and pre-emptive skin treatment which included skin moisturizer, sunscreen, 1% hydrocortisone cream, and an oral antibiotic for 6 weeks starting 24 hours prior to chemotherapy.

Participants received either FOLFIRI and panitumumab 6 mg/kg Q2W or irinotecan and panitumumab 9 mg/kg Q3W. Participants were treated for each individual skin toxicity occurrence according to prespecified guidelines and based on the type and severity. Treatment could include emollient, sunscreen, topical or oral steroids, antibiotics, or antihistamines, as required.

Recommended dosage regimen and administration of irinotecan was based on local standard of care, the package insert, and institutional guidelines.

Chemotherapy consisting of irinotecan with infusional 5-fluorouracil and leucovorin. Recommended dosage regimen and administration of FOLFIRI was based on local standard of care, the package insert for each product, and institutional guidelines.

FOLFIRI

Pre-emptive skin treatment included a skin moisturizer (eg, Lubriderm), sunscreen (free of paraaminobenzoic acid (PABA), skin protection factor (SPF) 15 or higher, ultraviolet-A (UV-A), and UV-B protection), topical steroid (1% hydrocortisone cream) and oral antibiotic (doxycycline, 100 mg twice daily).

Pre-emptive Skin Treatment

Treatment was based on symptoms and severity and may have included an emollient (eg, Lubriderm, Vaseline), sunscreen (SPF ≥ 15), oral antibiotic (eg, doxycycline, ciprofloxacin, cefadroxil, amoxicillin/clavulanic acid), topical steroid (hydrocortisone cream), topical antibiotic (clindamycin), oral systemic steroid, topical medical treatment (eg, silver sulfadiazine, Silvadene), topical antihistamine or oral antihistamine (hydroxyzine)

Reactive Skin Treatment

A comparison of prophylactic treatment with reactive treatment for skin toxicity observed in patients with metastatic colorectal cancer (mCRC) who are receiving second-line irinotecan-based chemotherapy concomitantly with panitumumab.

Skin Toxicity Treatment in Metastatic Colorectal Cancer (mCRC) Patients Receiving Panitumumab + Irinotecan-based Therapy

A Phase 2, Open-label, Randomized Clinical Trial of Skin Toxicity Treatment in Subjects Receiving Second-line FOLFIRI or Irinotecan Only Chemotherapy Concomitantly With Panitumumab

Skin toxicities were assessed by the study clinician and graded according to the modified Common Toxicity Criteria for Adverse Events (CTCAE) v.3.0 Dermatology Toxicity Grading criteria, on a scale from Grade 1 (mild) to 4 (life-threatening). The specific skin toxicities of interest were pruritus, acneiform dermatitis, skin desquamation (also described as skin exfoliation), exfoliative dermatitis, paronychia, nail disorder, skin fissures, skin laceration, pruritic rash, pustular rash, skin infection, skin ulceration, and local infection.

The percentage of participants who developed at least 1 incidence of ≥ grade 2 skin toxicities of any type during the 6-week skin treatment period. Analysis of this endpoint was based on adverse event data associated with the "Skin and Subcutaneous Tissue Disorders" system organ class. Adverse events were graded according to the National Cancer Institute (NCI) CTCAE version 3.0.

The time to the first occurrence of specific grade 2 or higher skin toxicities of interest was defined as the time from the first dose of panitumumab to the date of first occurrence of specific ≥ grade 2 skin toxicities of interest. Participants who did not experience specific skin-related toxicities were censored at their last skin toxicity assessment during the skin toxicity assessment period. Skin toxicities were assessed by the study clinician and graded according to the modified CTCAE v.3.0 Dermatology Toxicity Grading criteria, on a scale from Grade 1 (mild) to 4 (life-threatening). The specific skin toxicities of interest were pruritus, acneiform dermatitis, skin desquamation (also described as skin exfoliation), exfoliative dermatitis, paronychia, nail disorder, skin fissures, skin laceration, pruritic rash, pustular rash, skin infection, skin ulceration, and local infection.

The percentage of participants with a most severe grade of 2, 3 or 4 specific skin toxicity of interest reported during the 6-week skin treatment period. Skin toxicities were assessed by the study clinician and graded according to the modified CTCAE v.3.0 Dermatology Toxicity Grading criteria, on a scale from Grade 1 (mild) to 4 (life-threatening). The specific skin toxicities of interest were pruritus, acneiform dermatitis, skin desquamation (also described as skin exfoliation), exfoliative dermatitis, paronychia, nail disorder, skin fissures, skin laceration, pruritic rash, pustular rash, skin infection, skin ulceration, and local infection.

Time to the first most severe grade ≥ 2 of all the specific skin-related toxicities of interest was defined as the time from the first dose of panitumumab to the date of the first occurrence of the most severe specific ≥ grade 2 skin toxicity of interest during the 6-week skin treatment period. Participants who did not experience any specific skin-related toxicity of grade ≥ 2 were censored at their last skin toxicity assessment during the 6-week skin toxicity assessment period. Skin toxicities were assessed by the study clinician and graded according to the modified CTCAE v.3.0 Dermatology Toxicity Grading criteria, on a scale from Grade 1 (mild) to 4 (life-threatening). The specific skin toxicities of interest were pruritus, acneiform dermatitis, skin desquamation (also described as skin exfoliation), exfoliative dermatitis, paronychia, nail disorder, skin fissures, skin laceration, pruritic rash, pustular rash, skin infection, skin ulceration, and local infection.

Tumor response was assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI) of the abdomen, pelvis, and all other sites of disease. Disease assessments were performed by central review according to the modified response evaluation criteria in solid tumors (RECIST). Response rate is defined as the percentage of participants with a complete response (CR) or partial response (PR) at the Week 9/10 assessment visit and a corresponding CR or PR confirmed at the Week 13/14 assessment visit for the Q2W/Q3W regimens. CR: Disappearance of all target and non-target lesions and no new lesions. PR: Either the disappearance of all target lesions with persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease (PD; ≥ 25% increase in lesion size) and no new lesions, or, at least a 30% decrease in the size of target lesions with no progression of existing non-target lesions, and no new lesions.

Best overall response rate is defined as the percentage of participants with a complete response (CR) or partial response (PR) while on study. Tumor response was assessed by CT scan or MRI of the abdomen, pelvis, and all other sites of disease. Disease assessments were performed by central review according to the modified RECIST criteria. CR: Disappearance of all target and non-target lesions and no new lesions. PR: Either the disappearance of all target lesions with persistence of one or more non-target lesion(s) not qualifying for either CR or PD (≥ 25% increase in lesion size) and no new lesions, or, at least a 30% decrease in the size of target lesions with no progression of existing non-target lesions, and no new lesions.

Tumor response was assessed by CT scan or MRI of the abdomen, pelvis, and all other sites of disease. Disease assessments were performed by central review according to the modified response evaluation criteria in solid tumors (RECIST). Disease control rate is defined as the percentage of participants with a CR, PR or stable disease (SD) at the Week 9/10 assessment visit and a corresponding response (CR or PR) confirmed at the Week 13/14 assessment visit for the Q2W/Q3W regimens. SD: Neither sufficient shrinkage or increase in target lesions to qualify for PR or PD, with no progression of non-target lesions and no new lesions.

Time-to-treatment failure is defined as the time from the date of randomization to the first date of any of the following events: discontinuation of study therapy due to any reason (except for complete response and curative surgery), progression of disease, or death due to any cause. Participants who did not discontinue, who were still alive, and who did not have disease progression were censored at the date of last contact. Time to treatment failure was analyzed using the Kaplan-Meier method.

Time from the date of randomization to the date of observed disease progression or death due to disease progression. Participants who did not have documented disease progression were censored at the date of last tumor assessment; participants who died for reasons other than disease progression while on study were censored at the date of death. PD: At least a 20% increase in the size of target lesions, recorded since the treatment started, or at least a 25% increase in size of non-target lesions and the lesion(s) measure \> 10 mm in one dimension, or the appearance of one or more new lesions.

Time to progression was analyzed using the Kaplan-Meier method. This analysis excludes any data collected during follow-up for participants who began third-line treatment.

Overall Survival is defined as the time from the date of randomization to the date of death. Participants who did not die while on study or who were lost-to-follow-up were censored at their last contact date. Overall survival was analyzed using all data regardless of whether it was collected during second- or third-line treatment.

Defined as the time from the date of randomization to the first date of observed disease progression or death due to any cause (whichever comes first). Participants who were alive and had not progressed while on study were censored at the date of last progression-free tumor assessment.

Skin-related quality of life was assessed using the DLQI. The DLQI questionnaire asks participants to evaluate the degree that their skin condition has affected their quality of life in the last week. Participants answer 10 questions on a scale from 0 (not at all) to 3 (very much); The DLQI score is calculated by summing the scores for all questions, resulting in a maximum of 30 and a minimum of 0; higher scores indicate a more impaired quality of life.

Amgen

Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

Total

Age, Continuous

Sex: Female, Male

White or Caucasian

Black or African American

Hispanic or Latino

Asian

Native Hawaiian or other Pacific Islander

Other

Race/Ethnicity, Customized

FOLFIRI + Panitumumab Q2W

Irinotecan + Panitumumab Q3W

Chemotherapy Stratification

Study Director

Primary analysis set (all randomized participants who provided informed consent before protocol-specific procedures and who received at least 1 dose of panitumumab)

Percentage of Participants With Specific Grade 2 or Higher Skin Toxicities During the 6-week Skin Treatment Period

Percentage of Participants With Any Grade 2 or Higher Skin Toxicity of Any Type During the 6-week Skin Treatment Period

Time to First Occurrence of Specific Grade 2 or Higher Skin Toxicities of Interest

Grade 2

Grade 3

Grade 4

Most Severe Specific Grade 2 or Higher Skin Toxicities of Interest

Time to First Most Severe Specific Grade 2 or Higher Skin Toxicities of Interest

Percentage of Participants With Panitumumab Dose Reductions Due to the Specific Skin Toxicities of Interest

Primary Analysis Set; participants who discontinued prematurely without a post-baseline tumor assessment or with an observed CR or PR at Week 9 or 10 that was not confirmed at Week 13/14 were considered non-responders.

Response Rate at First Scheduled Assessment

Primary Analysis Set; participants who prematurely discontinued without a post-baseline tumor assessment or with an observed CR or PR that was not confirmed were considered non-responders.

Best Overall Response Rate

Primary Analysis Set; participants who prematurely discontinued without a postbaseline tumor assessment or with an observed CR or PR at Week 9 or 10 that was not confirmed at Week 13 or 14 were considered non-responders.

Rate of Disease Control at First Scheduled Assessment

Time to Treatment Failure

Time to Progression

Overall Survival

Progression-free Survival

Baseline (n=46, 44)

Change from Baseline to Week 2 (n=42, 41)

Change from Baseline to Week 3 (n=44, 42)

Change from Baseline to Week 4 (n=42, 42)

Change from Baseline to Week 5 (n=44, 42)

Change from Baseline to Week 6 (n=42, 38)

Change from Baseline to Week 7 (n=40, 40)

Patient Reported Outcomes (PRO) Analysis Set (randomized participants who signed informed consent before protocol-specified procedures, received at least 1 dose of panitumumab, with a non-missing baseline overall DLQI score and who had at least 1 post-baseline non-missing overall DLQI score) with available data at each time point.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pre-emptive Low-dose Doxycycline During Anti-EGFR Treatment	NCT01380262	Colorectal Canc... Skin Toxicities		18 Years - 85 Years	Maria Sklodowska-Curie National Research Institute of Oncology
Skin Toxicity Treatment in Metastatic Colorectal Cancer (mCRC) Patients Receiving Panitumumab + Irinotecan-based Therapy	NCT00332163	Metastatic Colo... Skin Rash Skin Toxicities Colon Cancer Colorectal Canc...	Panitumumab Irinotecan FOLFIRI Pre-emptive Ski... Reactive Skin T...	18 Years - 90 Years	Amgen
Pre-emptive Low-dose Doxycycline During Anti-EGFR Treatment	NCT01380262	Colorectal Canc... Skin Toxicities		18 Years - 85 Years	Maria Sklodowska-Curie National Research Institute of Oncology

Spots Global Cancer Trial Database for skin toxicities