Rhabdomyosarcoma. Disclosures. Abbreviations. COG Disclosure. Abbreviations. Objectives. Progress & Challenges in COG Clinical Trials

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1 1 Disclosures Rhabdomyosarcoma: Progress & Challenges in COG Clinical Trials Amy Newman and Shari Feinberg have no industry relationships relevant to this presentation Off label use will be discussed Shari Feinberg RN, MSN, CPNP, CPON Amy R. Newman, RN, MSN, CPNP COG Educational Track at APHON COG Disclosure The information in this presentation is intended for educational purposes only and is solely for the use of the individual nurse learner. This information is not intended as the sole source of guidance in providing Children s Oncology Group (COG) protocoldirected nursing care, and current COG protocols should always be consulted prior to making patient care decisions for any patient enrolled on a COG protocol. Learners should also be aware that COG protocols are research plans designed to investigate particular study questions, that recommendations for treatment and dosing are made within the context of specific research aims, and that these recommendations are intended only for use within a structured research setting. Although every attempt has been made to assure that the informational content contained herein is as accurate and complete as possible as of the date of presentation, no warranty or representation, express or implied, is made as to the accuracy, reliability, completeness, relevance, or timeliness of this content. This information may not be copied or redistributed in any form, or used for any purpose other than nursing education. Abbreviations Children's Oncology Group COG Radiation therapy XRT 18 fluoro-2-deoxy-d-glucose positron emission tomography FDG PET Cyclophosphamide CPM Dose limiting toxicity DLT Doxorubicin DOXO Etoposide ETOP Event free survival EFS Gastrointestinal GI Genitourinary GU Gross total resection GTR Growth hormone GH Hemoglobin A1C HgbA1C High risk HR Ifosfamide IFOS Ifosfamide, etoposide IE Insulin-like growth factor I receptor IGF-IR Intergroup rhabdomyosarcoma IRS Intergroup rhabdomyosarcoma study group IRSG Intermediate risk IR 3 4 Abbreviations Liver function tests Loss of heterozygosity Lymph node Maximum tolerated dose Memorial Sloan-Kettering Cancer Center Peripheral intravenous line Pneumocystis Carinii Rhabdomyosarcoma Subsequent malignant neoplasm Temozolomide Trimethoprim Urinary tract infection Vincristine, dactinomycin, cyclophosphamide Vincristine, dactinomycin, ifosfamide Vincristine, doxorubicin, cyclophosphamide Vincristine, ifosfamide, etoposide Vincristine, irinotecan Vincristine, irinotecan, temozolomide LFT LOH LN MTD MSKCC PIV PCP RMS SMN TMZ TMP UTI VAC VAI VADRIAC VIE VI VIT Objectives At the end of this activity, the learner will be able to Identify the overall treatment strategy for patients with rhabdomyosarcoma (RMS) Describe the basic outline of treatment according to the current High-Risk RMS protocol, ARST08P1, in lay language Identify possible side effects of the anti-igf-ir monoclonal antibody, IMC-A12, utilized in this protocol List common acute and late effects associated with treatment for RMS 5 6 Rhabdomyosarcoma: Progress and Challenges in Clinical Trials 1

2 7 Epidemiology & Risk Stratification RMS Incidence Most common soft tissue sarcoma of childhood 3-4% of all childhood cancers 350 new cases diagnosed annually in US 60% of cases in children < 6 yrs of age Histologic Subtypes Type/Incidence Most Common Site Embryonal (60%) Head/Neck GU Alveolar (20%) Botryoid Pleomorphic Trunk Extremities GU Adults Huh & Skapek, Risk Group Stratification Definitions Schema attempting to match treatment intensity to prognosis Relies on tumor characteristics before therapy and results of surgical intervention Incorporates Site Staging Histology Clinical Group Small round blue cell tumors of rhabdomyosarcoma 9 Term Favorable Unfavorable T1 and T2 a and b N0 and N1 NX M0 and M1 Definition Orbit (non parameningeal head and neck) GU (other than kidney, bladder, and prostate) Biliary tract Any site not listed as favorable in above Tumor confined to anatomical site of origin (T1) Tumor extension and/or fixation to surrounding tissue (T2) Tumor < 5 cm in diameter (a) Tumor > 5 cm in diameter (b) Presence (N1) or absence (N0) of regional LN Unable to assess regional lymph node status Presence (M1) or absence (M0) of metastasis TNM Staging Classification Stage Primary Site T Stage Tumor Size Regional LN I Favorable 1 or 2 Any N0, N1, NX Distant Metastasis M0 II Unfavorable 1 or 2 a, <5 cm N0, NX M0 III Unfavorable 1 or 2 a, <5 cm N1 M0 b, > 5 cm N0, N1, NX IV Any 1 or 2 Any N0, N1, NX M1 IRS Clinical Group Classification Group I Localized disease GTR Group II GTR with evidence of regional spread Microscopically positive margins or involved nodes (completely excised) 11 Illustrations by Alice Yang 12 Rhabdomyosarcoma: Progress and Challenges in Clinical Trials 2

3 13 IRS Clinical Group Classification Group III Incomplete resection with gross residual disease Biopsy only Group IV Distant metastases Illustrations by Alice Yang COG Risk Stratification Low Risk Intermediate Risk Metastases No No Yes Histology Embryonal Any Any Stage Clinical Group Group I or II Any stage Group III Stage 1 Stage 1 Group I, II, or III Stage 2 or 3 Group III Alveolar Stage 1, 2, or 3 Embryonal Stage 2 or 3 Stage 2 or 3 Group III Alveolar Group I, II, or III High Risk Stage 4 Group IV Barr & Womer, Cytogenetics Alveolar t(2;13)(q35;q14) PAX3-FKHR 55% of cases Worse prognosis t(1;13)(q36;q14) PAX7-FKHR 23% of cases Fusion negative Clinical outcomes similar to patients with embryonal histology Barr & Womer, 2009; Okcu, Hicks, & Horowitz, 2012; Skapek & Huh, 2010 Embryonal Specific translocations not identified LOH at chromosome 11p15 80% of cases Common to see loss or gain of chromosomes 50% gain of chromosome 8 Historical Perspective Low- and Intermediate-Risk Disease Where it all began Initially described by Weber in 1821 yet. Definitive publication by Stout in 1946 Stout, A. P. (1946). Rhabdomyosarcoma of the skeletal muscles. Annals of Surgery, 123, The Beginning IRSG Conducted the largest series of clinical trials for patients prior to merger of the pediatric cooperative groups Looked at Chemotherapy combinations Methods of delivering XRT Degree/timing of surgical resection Enrolled 4292 patients Rhabdomyosarcoma: Progress and Challenges in Clinical Trials 3

4 19 Historical Perspective of RMS Trials And the Studies Show Trial ERA IRS- I IRS- II IRS- III IRS- IV pilot (HR only) IRS- IV Raney, et al., 2001 Modality Surgery XRT Chemotherapy Findings May not be optimal for all patients (i.e., eye, bladder, vagina) Patients who are older at diagnosis are more likely to have a greater degree of regional LN involvement Best prognosis if: -Localized/GTR -Tumor free margins IRS-III & IV demonstrated improved outcomes in patients receiving intensified therapy No benefit for: -Completely resected/localized tumors -Hyperfractionated delivery VAC vs. VAI or VIE no difference in outcome BUT toxicity with VAI and VIE VAC = Gold Standard for LR/IR patients IE and VADRIAC added to VAC backbone for HR patients Raney, et al., Relapse 30% of patients will experience relapse 80% = unfavorable prognosis 10% overall survival at 5 years 20% = favorable prognosis Botryoid or Stage I, Group I embryonal histology 50% overall survival at 5 years Pappo, et al., 1999 The Problem Remains Unchanged or poor survival in IR, HR, and relapsed patients despite incorporation of new chemotherapeutic agents The Answer Lies on the Horizon High-Risk Rhabdomyosarcoma Refining risk stratification based on biology-based metrics Novel targeted therapies Clinical trials Huh & Skapek, Rhabdomyosarcoma: Progress and Challenges in Clinical Trials 4

5 25 High-Risk RMS High-Risk = metastatic disease at presentation Stage IV Clinical Group IV Incidence 16% of all cases of RMS Survival 5-year survival: 20-30% 3-year EFS = <20% in patients >10 yrs of age ARST08P1 A Pilot Study to Evaluate Novel Agents (Temozolomide (TMZ) and Cixutumumab [IMC-A12, Anti-IGF-IR Monoclonal Antibody]) in Combination with Intensive Multi-Agent Interval Compressed Therapy for Patients with High-Risk Rhabdomyosarcoma Oberlin, et al., ARST08P1: High-Risk RMS Purpose Evaluate the addition of novel agents to intensive chemotherapy backbone Pilot Studies Pilot 1 Pilot 2 Pilot 3 Addition of IGF-IR inhibitor, IMC-A12 Addition of TMZ Addition of IMC-A12 and TMZ 27 ARST08P1: Objectives Primary objectives to determine the feasibility of: Administering IMC-A12 in combination with a multi-agent intensive chemotherapy regimen Adding TMZ to VI cycles and to assess immediate and shortterm SEs of delivery of concurrent VIT with XRT Secondary objectives to: Estimate the response rate for IMC-A12 and/or TMZ plus VI Obtain efficacy data for IMC-A12 and/or TMZ in combination with an interval compressed chemotherapy regimen Determine effectiveness of detecting metastatic disease and response with FDG PET compared to standard imaging Assess changes in serum levels of IGF-I, IGF-II, IGF-BP3 as biomarkers of IGF-IR inhibition ARST08P1: Eligibility Newly diagnosed, biopsy proven metastatic RMS or ectomesenchymoma Less than 50 years old Must enroll on biology study COG-D9902 No prior chemotherapy or radiation therapy Steroids and emergent XRT acceptable Not Eligible Patients with uncontrolled infections Patients with known Type I or II diabetes mellitus are NOT eligible for Pilot 1 or 3. ARST08P1: Chemotherapy Backbone Based on previous High-Risk RMS study, ARST0431 Incorporates all agents known to be active in RMS Vincristine, irinotecan, doxorubicin, CPM, ifosfamide, etoposide VADRIAC and IE administered in an interval compression model Rhabdomyosarcoma: Progress and Challenges in Clinical Trials 5

6 31 ARST08P1: Local Control XRT XRT to primary and metastatic sites at Week 20 Surgery Generally biopsy only Second look surgery Possible for patients with stable or resolving metastatic disease Must aim for complete resection without significant loss of function or cosmesis Timing: After Week 19 evaluations & before starting Week 20 chemotherapy and XRT IMC-A12 Cixutumumab Fully humanized IgG1 monoclonal antibody targeting IGF-IR IGF-IR Transmembrane receptor kinase Promotes tissue growth by mediating the effects of IGF-I and IGF-II ligands Ligand binding results in cellular proliferation and inhibition of apoptosis McKian & Haluska, 2009 Structure of the IGF1R protein 32 IMC-A12 (continued) Inhibits ligand binding to IGF-IR resulting in Decreased proliferation of cancer cell lines Suppressed downstream signaling of P13k and MAPK pathways Suppressed tumor growth Malempati et al., 2012 Illustration by Aimee Ermel IMC-A12 Phase I Trials Phase I adult trial MTD not reached Most significant adverse event: HYPERGLYCEMIA Recommended adult dose: 6mg/kg weekly Phase I pediatric trial (ADVL0712) Children with refractory solid tumors One DLT at 6mg/kg and none at 9mg/kg Grade 2 or higher toxicities Anemia, leukopenia, lymphopenia, neutropenia, opportunistic infection, elevated LFTs, hyperglycemia Recommended Phase II dose: 9mg/kg weekly Higano, et al., 2007; Malempati, et al., IMC-A12: Administration IV infusion over 1 hour (infusion rate not to exceed 25mg/min via PIV or central line) Dilutions based on age and dose Administer with an in-line protein-sparing filter Flush following infusion with 0.9% NaCl Pre-medication NOT required unless previous history of reaction Administer after other chemotherapy is given Hold during XRT IMC-A12: Toxicities Likely toxicities (>20% of patients) Fatigue Hyperglycemia Less likely (< 20% of patients) Infusion-related reactions Allergic reactions Anaphylactic reactions (<3%) Rhabdomyosarcoma: Progress and Challenges in Clinical Trials 6

7 37 Hyperglycemia Based on random, non-fasting glucose levels Grade 1 or 2 Consider Endocrine consult No changes in IMC-A12 dosing Grade 3 (blood glucose > mg/dL or urine glucose >0.1g/dL) Initiate insulin or oral diabetic agent Hold IMC-A12 until resolves to < Grade 2 without glycosuria Resume at same dose IF Asymptomatic AND serum glucose consistently remains <250mg/dL without glycosuria May continue to receive concomitant insulin or oral diabetic agent If Grade 3 hyperglycemia recurs, subsequent doses of IMC-A12 should be administered with one dose reduction. 37 Hyperglycemia (continued) Grade 4 Initiate insulin therapy as indicated Hold IMC-A12 until resolves to < Grade 2 Resume IMC-A12 with one dose reduction IF Patient is asymptomatic and serum glucose is consistently <250mg/dL without glycosuria May continue to receive concomitant insulin or oral diabetic agent Goal of insulin/oral diabetic agents = fasting blood sugars <126mg/dL and HgbA1C <8%. 38 Allergic Reactions Grade Symptom 1 Transient flushing or rash, drug fever <38 C (<100.4 F) 2 Rash, flushing, urticaria, dyspnea, drug fever <38 C (<100.4 F) Urticaria Intervention Slow infusion rate by 50% Stop infusion Symptom control as needed: -diphenhydramine -acetaminophen -oxygen Resume infusion at 50% when reaction decreased to < grade 1 Pre-medicate with diphenhydramine for subsequent doses If grade 1-2 reactions reoccur add IV dexamethasone as premed Allergic Reactions Grade Symptom 3 Bronchospasm with or without urticaria Allergy-related edema/ angioedema Hypotension Intervention Stop infusion Medicate as indicated: -dexamethasone IV(0.2 mg/kg /max 10 mg) -bronchodilators -other supportive care medications Consider hospitalization for observation Discontinue IMC-A12 4 Anaphylaxis Stop infusion Medicate as indicated: -dexamethasone IV(0.2 mg/kg /max 10 mg) -epinephrine and bronchodilators -other supportive care medications Consider hospitalization for observation Discontinue IMC-A Non-Hematologic Toxicities No dose modifications for the following Diarrhea Anorexia Weight loss Dehydration Nausea/Vomiting Mucositis/Stomatitis Fever or febrile neutropenia Temozolomide Second generation imidazotetrazine prodrug Undergoes spontaneous hydrolysis to the active metabolite, MTIC Methylates DNA at O 6 guanine and other sites Found to have synergy with irinotecan Activity of irinotecan can be improved with pre-treatment with temozolomide Reaches peak concentration in 1 hour Danson & Middleton, 2001 Chemical structure of temozolomide Rhabdomyosarcoma: Progress and Challenges in Clinical Trials 7

8 43 Temozolomide (continued) Irinotecan, temozolomide, and vincristine initially tested as 2-week regimen MSKCC studied temozolomide and irinotecan Administered daily x5 Found to be feasible with limited toxicities GI Myelosuppression Kushner, Kramer, Modak, & Cheung, 2006 Temozolomide: Administration Administer on empty stomach Food decreases rate and extent of absorption If cannot swallow capsules May be formulated by pharmacist into suspension May mix contents of capsule with apple sauce or apple juice All mixing should be done with disposable containers and utensils 44 Temozolomide: Prescribing/Dispensing Temozolomide: Side Effects Only dispense what is needed for each course Clearly indicate number of capsules to be taken Clearly indicate which days temozolomide will/will not be taken Each strength capsule will be dispensed in a separate, dark container Common Less Common N&V Anorexia Constipation Myelosuppression Alopecia Diarrhea Mucositis Lethargy Rash/Itching Hepatotoxicity Abdominal pain Peripheral edema Urinary frequency/uti ARST08P1: Study Status Progress Opened January 2010 Exceeding accrual estimates No unexpected toxicities despite chemotherapy backbone Eligibility expanded to include patients with metastatic embryonal RMS < 10 years of age Nursing Considerations (Nutrition/Skin) Nutrition Support recommended for >10% weight loss GH not allowed Avoid megesterol Mucositis Patient education re: oral hygiene Dental consult especially if head/neck XRT Recommend removal of braces Skin Painless/Reversible nail sloughing with compressed regimen Painful inflammation/desquamation of the palms/soles If occurs therapy interval to 21 days; reattempt 14-day cycle Rhabdomyosarcoma: Progress and Challenges in Clinical Trials 8

9 49 Nursing Considerations (Diarrhea) If the following occurs during 1 st course of VI Grade 3 or 4 Colitis Diarrhea Vomiting Dehydration Weight loss Abdominal pain Begin cefixime/cefpodoxime 5 days prior to starting 2 nd course of chemotherapy (if not feasible, minimum 1 day prior) Continue PO antibiotics through Day 21 Management of both early and late diarrhea outlined in Supportive Care Guidelines (ARST08P1, Appendix X) Nursing Considerations (Infection) Hematopoietic growth factors Required for interval compression after VADRIAC and IE cycles Recommended after VAC (not after VI or VIT) Begin a full 24 hours following last dose of chemotherapy Subcutaneous preferred route PCP prophylaxis Bactrim (TMP 2.5mg/kg/dose; max 160mg) PO BID three consecutive days per week Switch to pentamidine during chemoradiotherapy when receiving temozolomide 50 Understanding Late Effects in RMS Late Effects of Treatment Broken down into two groups Those caused by Systemic therapy Local control therapy Location of tumor is KEY Late Effects (Infertility) Related to local control and/or systemic therapy Alkylating agents (systemic therapy) Ifosfamide Cyclophosphamide XRT (local therapy) Move testes or ovaries out of XRT field when possible Surgery (local therapy) Risk greater for boys than girls When feasible Sperm banking Egg harvesting Late Effects (Bladder Dysfunction) Related to local control and/or systemic therapy Chemotherapy (systemic) XRT and surgery (local) Toxicity Bladder fibrosis Hemorrhagic cystitis Dysfunctional voiding ~50% of patients will have symptoms Dribbling Illustration by Aimee Ermel Enuresis No predictors of the severity of the symptoms Illustration by Aimee Ermel Rhabdomyosarcoma: Progress and Challenges in Clinical Trials 9

10 55 Late Effects (Head and Neck) Related to local control with XRT Direct result of inability to obtain complete surgical resection due to location of tumor Common late effects Cataracts Chronic sinus infections Asymmetric facial growth Growth failure due to pituitary damage Complex and multiple dental abnormalities Late Effects (SMN) Chemotherapy Secondary leukemia Alkylating agents (CPM & IFOS) Topoisomerase II inhibitors (ETOP & DOXO) Bladder cancer (CPM ) XRT Skin Bladder Sarcoma CNS (benign or malignant) Underlying genetic disorders may predispose patients to developing a SMN Meningioma Illustration by Aimee Ermel Barr, F. G., & Womer, R. B. (2009). Rhabdomyosarcoma. In S. H. Orkin, D. E. Fisher, A. T. Look, S. E. Lux, D. Ginsburg, & D. G. Nathan (Eds.), Oncology of infancy and childhood (pp ). Philadelphia, PA: Saunders Elsevier. Breneman, J. C., Lyden, E., Pappo, A. S., Link, M. P., Anderson, J. R., Parham, D. M.,... Crist, V. M. (2003). Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma a report from the Intergroup Rhabdomyosarcoma Study IV. JCO, 21, Crist, W. M., Garnsey, L., Beltangady, M. S., Gehan, E., Ruymann, R., Webber, B.,... Maurer, H. M. (1990). Prognosis in children with rhabdomyosarcoma: a report of the Intergroup Rhabdomyosarcoma Studies I and II. Intergroup Rhabdomyosarcoma Committee. Journal of Clinical Oncology, 8, Crist, W., Gehan, E. A., Ragab, A. H., Dickman, P. S., Donaldson, S. S., Fryer, C.,... Heyn, R. (1995). The Third Intergroup Rhabdomyosarcoma Study. Journal of Clinical Oncology, 13, Danson, S.J., & Middleton, M.R. (2001). Temozolomide: a novel oral alkylating agent. Expert Reviews in Anticancer Therapy, 1(1), Higano, C.S., Yu, E.Y., Whiting, S.H., et al. (2007). A phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-i reception IgG1 monoclonal antibody in patients with advanced solid tumors. Journal of Clinical Oncology, 25, Huh, W. W., & Skapek, S. X. (2010). Childhood rhabdomyosarcoma: new insight on biology and treatment. Current Oncology Reports, 12, Kushner, B. H., Kramer, K., Modak, S., & Cheung, N. K. (2006). Irinotecan and temozolomide for relapsed or refractory neuroblastoma. Journal of Clinical Oncology, 24, Rhabdomyosarcoma: Progress and Challenges in Clinical Trials 10

11 61 Lawrence, W., Anderson, J. R., Gehan, E. A., & Maurer, H. (1997). Pretreatment TNM staging of childhood rhabdomyosarcoma: a report of the Intergroup Rhabdomyosarcoma Study Group. Children s Cancer Study Group. Pediatric Oncology Group. Cancer, 80, Lawrence, W., Gehan, E. A., Hays, D. M., Beltangady, M., & Maurer, H. M. (1987). Prognostic significance of staging factors of the UICC staging system in childhood rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study (IRS-II). Journal of Clinical Oncology, 5, Malempati, S., Weigel, B., Ingle, A.M., Ahern, C.H., Carroll, J.M., Roberts, C.T. (2012). Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma: a report from the Children's Oncology Group. Journal of Clinical Oncology, 30(3), McKian, K.P., & Haluska, P. (2009). Cixutumumab. Expert Opinion in Investigational Drugs, 18(7), Oberlin, O., Rey, A., Lyden., E., Bisogno, G., Stevens, M. C. G., Meyer, W. H.,... Anderson, J. R. (2008). Prognostic factors in metastatic rhabdomyosarcoma: results of a pooled analysis from the United States and European Cooperative Groups. Journal of Clinical Oncology, 26, Pappo, A. S., Anderson, J. R., Crist, W. M., Wharam, M. D., Breitfeld, P. P., Hawkins, D.,... Grier, H. E. (1999). Survival after relapse in children and adolescents with rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study Group. Journal of Clinical Oncology, 17, Raney, R. B., Anderson, J. R., Barr, F. G., Donaldson, S. S., Pappo, A. S., Qualman, S. J.,... Crist, W. M. (2001). Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of intergroup rhabdomyosarcoma study group experience and rationale for Intergroup Rhabdomyosarcoma Study V. Journal of Pediatric Hematology & Oncology, 23, Stout, A. P. (1946). Rhabdomyosarcoma of the skeletal muscles. Annals of Surgery, 123, Rhabdomyosarcoma: Progress and Challenges in Clinical Trials 11