APRIL 11-14, 2018 SWOG LYMPHOMA

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1 LYMPHOMA COMMITTEE APRIL 11-14, 2018 SWOG LYMPHOMA 1

2 CONTENTS S0816 Phase II... 6 S1608 Phase II EAY131 Master Protocol / Phase II APRIL 11-14, 2018 SWOG LYMPHOMA 2

3 Patient Registrations to Studies By 12 Month Intervals LYMPHOMA COMMITTEE Jan 2012 Dec Jan 2013 Dec Jan 2014 Dec 2014 SWOG LAPS MEMBER NCORP NON-SWOG Jan 2015 Dec 2015 Time of Registration Jan 2016 Dec Jan 2017 Dec 2017 Screening registrations and registrations to Biologic only studies are excluded. APRIL 11-14, 2018 SWOG LYMPHOMA 3

4 Patient Registrations by Study and Arm LYMPHOMA COMMITTEE Jul 2017 Dec 2017 Jan 2017 Jun 2017 Jul 2016 Dec 2016 All Patients S1001 DLBCL, I-II, PET-Adapted Therapy PET-Directed Therapy Continued R-CHOP IFRT + Zevalin A ABC DLBCL, Auto HCT and Ibrutinib/Placebo* Total Registrations C51101 CNS, Myelo/non-Myelo Chemo, PhII* Total Registrations E1411 MCL, RB+R, RBV+R, RB+LR, RBV+LR* Total Registrations E1412 DLBCL, R2CHOP vs RCHOP* Total Registrations * For non-swog coordinated studies only SWOG registrations are shown. APRIL 11-14, 2018 SWOG LYMPHOMA 4

5 Non-SWOG Studies with SWOG-Credited Registrations LYMPHOMA COMMITTEE Studies with Accrual from July December 2017 SWOG Champion Date Activated Date Closed Total Accrued 9177 NHL, Dose-Adj. EPOCH+/-Rituximab M Fanale 04/13/12 05/10/ No Progress Report Available A ABC DLBCL, Auto HCT and Ibrutinib/Placebo P. Stiff 07/15/16 23 No Progress Report Available C51101 CNS, Myelo/non-Myelo Chemo, PhII N Mohile 06/22/12 05/02/ Most Recent Progress Report E1411 MCL, RB+R, RBV+R, RB+LR, RBV+LR B Till 06/08/12 09/09/ Most Recent Progress Report E1412 DLBCL, R2CHOP vs RCHOP J Amengual 01/22/14 01/24/ Most Recent Progress Report EA4151 MCL, Auto-HCT+Rituximab vs. +Rituximab B Till 08/29/17 3 No Progress Report Available APRIL 11-14, 2018 SWOG LYMPHOMA 5

6 S0816 Phase II Coordinating Group: SWOG A Phase II Trial of Response-Adapted Therapy of Stage III-IV Hodgkin Lymphoma Using Early Interim FDG-PET Imaging Participants: SWOG, CTSU (Supported by AMC, Alliance, ECOG- ACRIN) Study Chairs: O Press, N Bartlett (Alliance), J Sweetenham (ECOG- ACRIN), M Lechowicz (AMC) Date Activated: 07/01/2009 Date Closed: 12/01/2012 Statisticians: H Li, M LeBlanc Data Coordinator: J Jardine SCHEMA R E G I S T E R ABVD X 2 PET- PET+ ABVD X 4 BEACOPP X 6* * HIV-negative patients will receive BEACOPP escalated * HIV-positive patients will receive BEACOPP standard Objectives The co-primary objectives are as follows: a. To estimate two-year progression-free survival (PFS) in HIV-negative patients with advanced stage Hodgkin lymphoma (HL) treated with responseadapted therapy based on FDG-PET imaging after two cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). b. To estimate two-year PFS in the subset of HIVnegative patients with advanced stage HL who are PET-positive after two cycles of ABVD and are subsequently treated with escalated dose BEACOPP. APRIL 11-14, 2018 SWOG LYMPHOMA 6

7 Secondary endpoints include the following: To estimate two-year overall survival (OS) for HIVnegative patients treated with response-adapted therapy. To estimate the response rate (complete and partial) for HIV-negative patients treated with responseadapted therapy. To evaluate the toxicity of this response-adapted regimen. To document the feasibility of centralized, real-time review of FDG-PET imaging for US cooperative group studies. To prospectively evaluate the overall response rate, complete response rate, PFS and OS in a cohort of HIV-positive patients with HL treated with responseadapted therapy. The use of cycle-2 PET scanning in HIV infection will be done to provide preliminary data for this strategy in HIV-infected patients. To prospectively identify serum and tissue biomarkers associated with PFS and OS in patients with HL treated with response-adapted therapy. Biologic features meriting specific investigation include the degree of tumor cell infiltration with T- regulatory cells, the FOXP3/Granzyme B ratio, and the expression of MAL or Bcl-2 in biopsy samples, and TARC levels in serum specimens. To prospectively evaluate HIV viral load and CD4 cells in the cohort of HIV-positive patients with HL treated with response-adapted therapy. Patient Population Patients must have histologically or cytologically confirmed classical Hodgkin lymphoma. Patients with nodular lymphocyte-predominant Hodgkin lymphoma are ineligible. Patients with CNS disease involvement are ineligible. Patients must not have received prior chemotherapy, radiation, or antibody therapy for lymphoma. Patients must have a Zubrod performance status of 0-2, be at least 18 and no more than 60 years of age, and have adequate cardiac and pulmonary function. Patients must not be sero-positive for Hepatitis B or C. HIV-positive patients are eligible if they do not have multi-drug resistant HIV infection, CD4 counts < 350/mcL or other concurrent AIDS-defining conditions. Stratification/Descriptive Factors Patients will be stratified by HIV-positivity: yes vs no. Accrual Goals As part of an amendment on August 1, 2011, the sample size for this study was increased. Patient accrual will continue until 60 eligible patients in the FDG-PET-positive subgroup are enrolled. Under the assumption that 17% of patients are FDG-PETpositive after two cycles of ABVD, this leads to a sample size of 350 eligible HIV-negative patients. The HIV-positive cohort will be analyzed separately, with maximum anticipated accrual of 30 eligible HIV-positive patients. Summary Statement This study was closed on December 1, 2012, after reaching full accrual. Three hundred seventy-one patients were registered to this study, including 358 HIV-negative patients and 13 HIV-positive patients. HIV-negative cohort: Of 358 HIV-negative patients, 20 patients are ineligible due to incorrect histology after centralized pathology review. Two additional patients who did not receive any protocol treatment are not analyzable and are excluded from all analyses. Two initial cycles of ABVD were completed as planned in 333 patients. Three patients discontinued the initial ABVD for the following reasons: one due to neutropenia, one refused treatment, and another one was non-compliant. Three hundred thirty-six HIV-negative patients were assessed for toxicity during the two initial cycles of ABVD. One hundred thirty-six patients experienced 4 toxicities, primarily hematologic. Of these, seven patients experienced the following 4 non-hematologic toxicities: blood infection (2 patients, coded as "Inf, 3-4 ANC: blood"), febrile neutropenia, abdomen pain (coded as "GI pain: abdomen"), lung infection (coded as "Lung inf, 3-4 ANC: mucosa"), chest wall pain (coded as "Lung Pain: chest wall"), agitation, depression, and nausea (1 patient each). Ninety-two patients experienced 3 toxicities as maximum degree. APRIL 11-14, 2018 SWOG LYMPHOMA 7

8 Among 336 evaluable patients who received two initial cycles of ABVD, eight patients who did not have response adequately assessed are assumed nonresponders for the purpose of response rate estimation. Two hundred forty-one complete responses and 76 partial responses were observed, for an estimated response rate of 94% (95% CI: 91.3%, 96.6%). After two initial cycles of ABVD, 343 patients registered to Step 2 of the study to receive responseadapted therapy, including 285 PET2-negative patients to receive four additional cycles of ABVD and 58 PET2-positive patients to receive six cycles of escalated BEACOPP (ebeacopp). Fifteen PET2- negative patients on the continued ABVD arm and three PET2-positive patients on the ebeacopp arm are ineligible because they were ineligible for the initial registration. Six PET2-positive patients who did not receive ebeacopp are coded as major protocol deviations and not evaluable for adverse events. Two hundred seventy patients on the continued ABVD arm were assessed for toxicity. One patient died due to treatment related pneumonitis. Ninetyeight patients experienced 4 toxicities, primarily hematologic. Of these, six patients experienced the following 4 non-hematologic toxicities: thrombosis/embolism (2 patients), acute respiratory distress syndrome (ARDS), allergic reaction, colitis, dyspnea, and lung infection (coded as "Lung inf, 0-2 ANC: lung") (1 patient each). Ninety-two patients experienced 3 toxicities as maximum degree. Forty-nine patients on the ebeacopp arm were assessed for toxicity. Two patient deaths were found upon central review to be definitely treatment-related: one patient died due to blood infection during the second treatment cycle and had also experienced 4 febrile neutropenia, another patient died due to pneumonitis and had also experienced 4 dyspnea. Forty-one additional patients experienced 4 toxicities, primarily hematologic. Of these, six patients experienced the following 4 nonhematologic toxicities: febrile neutropenia (2 patients), dizziness, hyponatremia, blood infection (coded as "Inf, 3-4 ANC: blood"), oral cavity (coded as "Mucositis, clin: oral cavity"), and sensory neuropathy (1 patient each). Five patients experienced 3 toxicities as maximum degree. Of 325 patients treated with two cycles of ABVD followed by response-adapted therapy, one patient on the ABVD arm and seven patients on the ebeacopp arm who did not have response adequately assessed are assumed non-responders for the purpose of response rate estimation. On the two cycles of ABVD followed by ABVD arm, 258 complete responses and 11 partial responses were observed, for an estimated response rate of 99.6% (95% CI: 97.9%, 100%). On the two cycles of ABVD followed by ebeacopp arm, 30 complete responses and 15 partial responses were observed, for an estimated response rate of 82% (95% CI: 69.1%, 90.9%). The median length of follow-up among HIV-negative patients last known to be alive is 5.4 years (range 2.1 months years). Eighty-four patients have either progressed or died, for an estimated 2-year progression-free survival of 79% (95% CI: 73.9%, 82.8%). There have been 19 deaths, for an estimated 2-year overall survival of 98% (95% CI: 95.2%, 98.8%). HIV-positive cohort: Of 13 HIV-positive patients enrolled, one patient is ineligible due to insufficient baseline documentation. All 12 eligible patients completed two initial cycles of ABVD and were assessed for toxicity during treatment. Eight patients experienced 4 toxicities including neutrophils (8), leukocytes (2), and hyponatremia (1). Two additional patients experienced 3 toxicities as maximum degree. Among 12 patients assessed for response during two initial cycles of ABVD, eight complete responses and four partial responses were observed, for an estimated response rate of 100% (95% CI: 73.5%, 100%). After two initial cycles of ABVD, 12 patients registered to Step 2 of the study to receive responseadapted therapy, including 11 PET2-negative to receive additional four cycles of ABVD and one PET2-positive patient to receive six cycles of standard BEACOPP. One PET2-negative patient is ineligible because the patient was ineligible for the initial registration. Nine out of ten PET2-negative patients completed additional four cycles of ABVD and one PET2-positive patient completed six cycles of standard BEACOPP as planned. One PET2- negative patient discontinued ABVD treatment due to progressive disease. Ten HIV-positive patients on the continued ABVD arm were assessed for toxicity. Six patients experienced the following 4 toxicities: APRIL 11-14, 2018 SWOG LYMPHOMA 8

9 neutrophils (5), anemia (2), leukocytes (2), and lymphopenia (1). Three additional patients experienced 3 toxicities as maximum degree. One patient on the standard BEACOPP arm experienced 4 leukocyte, lymphopenia, neutrophils and 3 anemia and urine track infection. Of ten HIV-positive patients treated with two initial cycles of ABVD followed by four additional cycles of ABVD, nine complete responses and one partial response were observed, for an estimated response rate of 100% (95% CI: 69.2%, 100%). The one patient treated with two initial cycles of ABVD followed by six cycles of standard BEACOPP achieved partial response. The median length of follow-up among HIV-positive patients last known to be alive is 5.3 years (range years). Four patients have either progressed or died, for an estimated 2-year progression-free survival of 83% (95% CI: 46.1%, 95.3%). There were no patient deaths in the first two years for a 100% estimated 2-year overall survival. Of 12 eligible HIVpositive patients, one patient death occurred at 4.5 years after registration. Initial Registrations By 3 Month Intervals Jul Sep 2009 Oct Dec 2009 Jan Mar 2010 Apr Jun 2010 Jul Sep 2010 Oct Dec 2010 Jan Mar 2011 Apr Jun 2011 Jul Sep 2011 Oct Dec 2011 Jan Mar 2012 Apr Jun 2012 Jul Sep 2012 Oct Dec 2012 Time of Registration Initial ABVD APRIL 11-14, 2018 SWOG LYMPHOMA 9

10 Registration by Institution Institutions Total Reg Institutions Rochester, Univ of 18 ECOG-ACRIN 71 MD Anderson CC 16 CTSU 24 Michigan, U of 13 AMC 4 PCRC NCORP 10 NRG 3 All Other SWOG Institutions 98 Total (46 Institutions) 371 ALLIANCE 114 Total Reg HIV-negative Cohort Registration, Eligibility, and Evaluability Initial Registration HIV-negative Patients Initial ABVD NUMBER REGISTERED 358 INELIGIBLE 20 ELIGIBLE 338 Not Analyzable 2 ADVERSE EVENT ASSESSMENT Evaluable 336 APRIL 11-14, 2018 SWOG LYMPHOMA 10

11 Patient Characteristics Initial Registration HIV-negative Patients Initial ABVD (n=336) AGE Median 32.1 Minimum 18.1 Maximum 60.9 SEX Males % Females % HISPANIC Yes 28 8% No % Unknown 35 10% RACE White % Black 32 10% Asian 7 2% Pacific Islander 3 1% Multi-Racial 3 1% Unknown 17 5% Treatment Summary Initial Registration HIV-negative Patients Initial ABVD NUMBER ON PROTOCOL TREATMENT 0 NUMBER OFF PROTOCOL TREATMENT 336 REASON OFF TREATMENT Treatment completed as planned 333 Adverse Event or side effects 1 Refusal unrelated to adverse event 1 Progression/relapse 0 Death 0 Other - not protocol specified 1 Reason under review 0 MAJOR PROTOCOL DEVIATIONS 0 APRIL 11-14, 2018 SWOG LYMPHOMA 11

12 Number of Patients with a Given Type and of Adverse Event Initial Registration HIV-negative Patients Adverse Events Unlikely or Not Related to Treatment Excluded APRIL 11-14, 2018 SWOG LYMPHOMA 12 Initial ABVD (n=336) ADVERSE EVENTS ALT AST Acne Alkaline phosphatase Allergic reaction Alopecia Anorexia Arthritis Ataxia Atelectasis Auditory/Ear-other Bilirubin Blood-other Blurred vision Bronchospasm Card Inf, 0-2 ANC: vein Cheilitis Cognitive disturbance Colitis, infectious Constipation Constitutional Symptoms-other Cough Creatinine Cytokine release syndrome Dehydration Dermatology-other Diabetes Diarrhea Diplopia Distension Dizziness Dry mouth Dry skin Dysphagia Dyspnea Ear Inf, Unk ANC: ext. ear Ear Inf, Unk ANC: mid. ear Ear Pain: middle ear Edema-head and neck Edema-limb Endocrine-other Erectile dysfunction Erythema multiforme

13 APRIL 11-14, 2018 SWOG LYMPHOMA 13 Initial ABVD (n=336) ADVERSE EVENTS Esophagitis Fatigue Febrile neutropenia Fever Flatulence Flushing GI Inf, 0-2 ANC: gums GI Inf, 0-2 ANC: tooth GI Inf, 3-4 ANC: gums GI Inf, 3-4 ANC: tooth GI Pain: abdomen GI Pain: anus GI Pain: dental GI Pain: oral cavity GI Pain: stomach GI-other GU Hemorrhage: urinary GU Inf, 0-2 ANC: bladder GU Inf, 3-4 ANC: UTI GU Pain: bladder Gastritis Hand-foot Heartburn Hemoglobin Hemorrhage-other Hemorrhoids Hiccoughs Hot flashes Hypercalcemia Hyperglycemia Hyperkalemia Hypermagnesemia Hypernatremia Hyperpigmentation Hypertension Hyperuricemia Hypoalbuminemia Hypocalcemia Hypoglycemia Hypokalemia Hypomagnesemia Hyponatremia Hypophosphatemia Hypotension Ileus Inf, 0-2 ANC: cath.-related Inf, 3-4 ANC: blood Infection-other Injection site reaction Insomnia Involuntary movement

14 APRIL 11-14, 2018 SWOG LYMPHOMA 14 Initial ABVD (n=336) ADVERSE EVENTS Irregular menses Left vent. diastolic dysfunct Left vent. systolic dysfunct Leukocytes Lung Hemorrhage: nose Lung Inf, 0-2 ANC: lung Lung Inf, 0-2 ANC: mucosa Lung Inf, 0-2 ANC: sinus Lung Inf, 0-2 ANC: up. airway Lung Inf, 3-4 ANC: mucosa Lung Inf, 3-4 ANC: pharynx Lung Inf, 3-4 ANC: sinus Lung Inf, 3-4 ANC: up. aero Lung Inf, 3-4 ANC: up. airway Lung Inf, Unk ANC: sinus Lung Pain: chest wall Lung Pain: chest/thorax Lung Pain: larynx Lung Pain: throat/phar/lar Lymphatic Pain: lymph node Lymphopenia Memory impairment Metabolic/Lab-other Mood alteration: agitation Mood alteration: anxiety Mood alteration: depression Mucositis, clin: oral cavity Mucositis, clin: pharynx Mucositis, funct: oral cav Mucositis, funct: pharynx Muscle weakness: whole body Musculo. Pain: back Musculo. Pain: bone Musculo. Pain: buttock Musculo. Pain: joint Musculo. Pain: limb Musculo. Pain: muscle Musculo. Pain: neck Musculoskeletal-other Nail changes Nasal/paranasal reactions Nausea Neuro Inf, 3-4 ANC: mening Neuro Pain: head/headache Neurology-other Neuropathy-motor Neuropathy-sensory Neutrophils Ocular-other PTT Pain-other

15 Initial ABVD (n=336) ADVERSE EVENTS Pain: NOS Pain: tumor pain Palpitations Periodontal Phlebitis Platelets Pneumonitis Pruritus Pulmonary-other Rash Renal-other Rhinitis Rigors/chills Salivary gland changes Sex/Rep Inf, 3-4 ANC: vagina Sexual/Repro. Pain: vagina Skin Inf, 0-2 ANC: skin Skin Inf, 3-4 ANC: lip/perior Skin Inf, 3-4 ANC: skin Skin Pain: gums Supra Arrhyth: Atrial Tachy Supra Arrhyth: Sinus Tachy Sweating Syncope Taste alteration Thrombosis/embolism Thrombosis/embolism (vasc acc) Trismus Ulceration Urinary frequency Vaginal discharge Vascular-other Voice changes Vomiting Watery eye Weight Loss Weight gain MAX. GRADE ANY ADVERSE EVENT APRIL 11-14, 2018 SWOG LYMPHOMA 15

16 Response Initial Registration HIV-negative Patients Initial ABVD N % Complete Response Partial Response Stable/No Response 11 3 Assessment Inadequate 8 2 Total Registration, Eligibility, and Evaluability Continued Therapy HIV-negative Patients TOTAL Continued ABVD BEACOPP NUMBER REGISTERED INELIGIBLE ELIGIBLE ADVERSE EVENT ASSESSMENT Evaluable Not Evaluable Treatment Summary Continued Therapy HIV-negative Patients TOTAL Continued ABVD BEACOPP NUMBER ON PROTOCOL TREATMENT NUMBER OFF PROTOCOL TREATMENT REASON OFF TREATMENT Treatment completed as planned Adverse Event or side effects Refusal unrelated to adverse event Progression/relapse Death Other - not protocol specified Reason under review MAJOR PROTOCOL DEVIATIONS APRIL 11-14, 2018 SWOG LYMPHOMA 16

17 Number of Patients with a Given Type and of Adverse Event Continued Therapy HIV-negative Patients Adverse Events Unlikely or Not Related to Treatment Excluded Continued ABVD (n=270) APRIL 11-14, 2018 SWOG LYMPHOMA 17 BEACOPP (n=49) ADVERSE EVENTS ALT ARDS AST Acne Alkaline phosphatase Allergic reaction Alopecia Anorexia Ataxia Auditory/Ear-other Bilirubin Blood-other Blurred vision Bronchospasm Cardiac Arrhythmia-other Cardio. Pain: cardiac/heart Chest tube drainage or leak Cognitive disturbance Colitis Colitis, infectious Constipation Constitutional Symptoms-other Cough Creatinine Cushingoid Cystitis DLCO Dehydration Dermatology-other Diabetes Diarrhea Diplopia Distension Dizziness Dry eye Dry mouth Dry skin Dysphagia Dyspnea Ear Inf, 0-2 ANC: mid. ear Ear Pain: external ear Ear Pain: middle ear Edema-head and neck

18 Continued ABVD (n=270) APRIL 11-14, 2018 SWOG LYMPHOMA 18 BEACOPP (n=49) ADVERSE EVENTS Edema-limb Endocrine-other Erectile dysfunction Erythema multiforme Esophagitis Eye Inf, 3-4 ANC: conjunct Eye Pain: eye FEV Fatigue Febrile neutropenia Fever Flatulence Flu-like syndrome GI Hemorrhage: rectum GI Inf, 0-2 ANC: gums GI Inf, 0-2 ANC: stomach GI Inf, 0-2 ANC: tooth GI Inf, 3-4 ANC: anal/perian GI Inf, 3-4 ANC: colon GI Inf, 3-4 ANC: gums GI Inf, 3-4 ANC: stomach GI Inf, Unk ANC: gums GI Pain: abdomen GI Pain: dental GI Pain: esophagus GI Pain: oral cavity GI Pain: rectum GI Pain: stomach GI Ulcer: stomach GI-other GU Hemorrhage: urinary GU Hemorrhage: vagina GU Inf, 0-2 ANC: UTI GU Inf, 0-2 ANC: bladder GU Inf, 3-4 ANC: UTI GU Inf, Unk ANC: UTI GU Pain: bladder Gastritis Hand-foot Hearing (w/o monit. prog.) Heartburn Hemoglobin Hemolysis Hemorrhoids Hiccoughs Hot flashes Hypercalcemia Hyperglycemia Hyperkalemia Hypernatremia Hyperpigmentation

19 Continued ABVD (n=270) APRIL 11-14, 2018 SWOG LYMPHOMA 19 BEACOPP (n=49) ADVERSE EVENTS Hypertension Hypertriglyceridemia Hyperuricemia Hypoalbuminemia Hypocalcemia Hypoglycemia Hypokalemia Hypomagnesemia Hyponatremia Hypophosphatemia Hypopigmentation Hypotension Hypoxia Incontinence, urinary Induration Inf, 3-4 ANC: blood Infection-other Injection site reaction Insomnia Irregular menses Irritability Joint-function Left vent. diastolic dysfunct Left vent. systolic dysfunct Leukocytes Lung Hemorrhage: lung Lung Hemorrhage: nose Lung Inf, 0-2 ANC: lung Lung Inf, 0-2 ANC: mucosa Lung Inf, 0-2 ANC: sinus Lung Inf, 0-2 ANC: up. airway Lung Inf, 3-4 ANC: lung Lung Inf, 3-4 ANC: mucosa Lung Inf, 3-4 ANC: pharynx Lung Inf, 3-4 ANC: sinus Lung Inf, 3-4 ANC: up. aero Lung Inf, 3-4 ANC: up. airway Lung Inf, Unk ANC: bronchus Lung Inf, Unk ANC: lung Lung Inf, Unk ANC: nose Lung Inf, Unk ANC: sinus Lung Inf, Unk ANC: up. airway Lung Pain: chest wall Lung Pain: chest/thorax Lung Pain: sinus Lung Pain: throat/phar/lar Lymphatics-other Lymphopenia Memory impairment Metabolic/Lab-other Mood alteration: agitation

20 Continued ABVD (n=270) APRIL 11-14, 2018 SWOG LYMPHOMA 20 BEACOPP (n=49) ADVERSE EVENTS Mood alteration: anxiety Mood alteration: depression Mucositis, clin: oral cavity Mucositis, clin: pharynx Mucositis, funct: esophagus Mucositis, funct: oral cav Mucositis, funct: pharynx Musc Inf, 3-4 ANC: soft tissue Musc Inf, Unk ANC: soft tiss Muscle weakness: extraocular Muscle weakness: low. extrem Muscle weakness: up. extrem Muscle weakness: whole body Musculo. Pain: back Musculo. Pain: bone Musculo. Pain: joint Musculo. Pain: limb Musculo. Pain: muscle Musculo. Pain: neck Musculoskeletal-other Nail changes Nasal/paranasal reactions Nausea Neuro Pain: head/headache Neurology-other Neurop: smell Neuropathy-motor Neuropathy-sensory Neutrophils Ocular-other Opportunistic infection Osteonecrosis PTT Pain-other Pain: NOS Pain: tumor pain Palpitations Petechiae Phlebitis Photophobia Photosensitivity Platelets Pleural effusion Pneumonitis Proteinuria Pruritus Pulmonary fibrosis Pulmonary-other Rash Renal-other Rhinitis

21 Continued ABVD (n=270) BEACOPP (n=49) ADVERSE EVENTS Rigors/chills Salivary gland changes Sex/Rep Inf, 0-2 ANC: vagina Sex/Rep Inf, 3-4 ANC: vagina Sexual-other Skin Inf, 0-2 ANC: skin Skin Inf, 3-4 ANC: lip/perior Skin Inf, 3-4 ANC: skin Skin Inf, 3-4 ANC: ungual Skin Inf, Unk ANC: skin Skin Pain: face Skin Pain: gums Skin Pain: scalp Skin Pain: skin Supra Arrhyth: NOS Supra Arrhyth: Sinus Tachy Sweating Syncope Taste alteration Thrombosis/embolism Tinnitus Tremor Ulceration Urinary frequency Vaginal discharge Vent Arrhyth: Vent Tachy Vital capacity Voice changes Vomiting Watery eye Weight Loss Weight gain MAX. GRADE ANY ADVERSE EVENT Response Two Initial Cycles of ABVD Followed by Response-adapted Therapy HIV-negative Patients Continued ABVD BEACOPP N % N % Complete Response Partial Response Stable/No Response Assessment Inadequate Total APRIL 11-14, 2018 SWOG LYMPHOMA 21

22 100% Progression-Free Survival HIV-negative Patients 80% 60% 40% 20% 0% At Risk 336 Failed 84 2-Year Estimate 79% At Risk At Risk Months After Registration Stratum The LIFETEST 1: rowno = Procedure Initial ABVD Overall Survival HIV-negative Patients 100% 80% 60% 40% 20% 0% At Risk 336 Deaths 19 2-Year Estimate 98% At Risk At Risk Months After Registration APRIL 11-14, 2018 SWOG LYMPHOMA 22

23 HIV-positive Cohort Registration, Eligibility, and Evaluability Initial Registration HIV-positive Patients Initial ABVD NUMBER REGISTERED 13 INELIGIBLE 1 ELIGIBLE 12 ADVERSE EVENT ASSESSMENT Evaluable 12 Patient Characteristics Initial Registration HIV-positive Patients Initial ABVD (n=12) AGE Median 44.6 Minimum 25.2 Maximum 50.3 SEX Males 10 83% Females 2 17% HISPANIC Yes 3 25% No 8 67% Unknown 1 8% RACE White 5 42% Black 4 33% Unknown 3 25% APRIL 11-14, 2018 SWOG LYMPHOMA 23

24 Treatment Summary Initial Registration HIV-positive Patients Initial ABVD NUMBER ON PROTOCOL TREATMENT 0 NUMBER OFF PROTOCOL TREATMENT 12 REASON OFF TREATMENT Treatment completed as planned 12 Adverse Event or side effects 0 Refusal unrelated to adverse event 0 Progression/relapse 0 Death 0 Other - not protocol specified 0 Reason under review 0 MAJOR PROTOCOL DEVIATIONS 0 Number of Patients with a Given Type and of Adverse Event Initial Registration HIV-positive Patients Adverse Events Unlikely or Not Related to Treatment Excluded Initial ABVD (n=12) ADVERSE EVENTS Alkaline phosphatase Alopecia Anorexia Colitis, infectious Confusion Constipation Creatinine Cytokine release syndrome Dehydration Diarrhea Dizziness Dyspnea Eye Inf, 3-4 ANC: eye Fatigue Febrile neutropenia Fever GI Pain: abdomen Gastritis Hemoglobin Hot flashes Hyperglycemia APRIL 11-14, 2018 SWOG LYMPHOMA 24

25 Initial ABVD (n=12) ADVERSE EVENTS Hypertension Hypocalcemia Hypoglycemia Hypokalemia Hyponatremia Hypophosphatemia Hypotension Insomnia Leukocytes Libido Lymphopenia Mood alteration: agitation Mood alteration: anxiety Mucositis, clin: oral cavity Mucositis, funct: oral cav Muscle weakness: whole body Musculo. Pain: back Musculo. Pain: bone Musculo. Pain: joint Musculo. Pain: muscle Nail changes Nausea Neuro Pain: head/headache Neuropathy-motor Neuropathy-sensory Neutrophils Phlebitis Platelets Pruritus Rash Rigors/chills Supra Arrhyth: Sinus Tachy Sweating Urinary frequency Vomiting Weight Loss MAX. GRADE ANY ADVERSE EVENT Response Initial Registration HIV-positive Patients Initial ABVD N % Complete Response 8 67 Partial Response 4 33 Total APRIL 11-14, 2018 SWOG LYMPHOMA 25

26 Registration, Eligibility, and Evaluability Continued Therapy HIV-positive Patients TOTAL Continued ABVD BEACOPP NUMBER REGISTERED INELIGIBLE ELIGIBLE ADVERSE EVENT ASSESSMENT Evaluable Treatment Summary Continued Therapy HIV-positive Patients TOTAL Continued ABVD BEACOPP NUMBER ON PROTOCOL TREATMENT NUMBER OFF PROTOCOL TREATMENT REASON OFF TREATMENT Treatment completed as planned Adverse Event or side effects Refusal unrelated to adverse event Progression/relapse Death Other - not protocol specified Reason under review MAJOR PROTOCOL DEVIATIONS APRIL 11-14, 2018 SWOG LYMPHOMA 26

27 Number of Patients with a Given Type and of Adverse Event Continued Therapy HIV-positive Patients Adverse Events Unlikely or Not Related to Treatment Excluded Continued ABVD (n=10) APRIL 11-14, 2018 SWOG LYMPHOMA 27 BEACOPP (n=1) ADVERSE EVENTS ALT AST Alkaline phosphatase Alopecia Anorexia Bicarbonate, serum-low CD4 count Constipation Cough Creatinine DLCO Diarrhea Dizziness Dyspnea Fatigue Febrile neutropenia Fever GI Pain: abdomen GI Pain: oral cavity GU Inf, Unk ANC: UTI Heartburn Hemoglobin Hot flashes Hyperglycemia Hypertension Hypoalbuminemia Hypocalcemia Hypokalemia Hypomagnesemia Hyponatremia Hypophosphatemia Hypotension Leukocytes Libido Lung Inf, 3-4 ANC: lung Lung Pain: chest/thorax Lung Pain: throat/phar/lar Lymphopenia Metabolic/Lab-other Mood alteration: anxiety Mood alteration: depression Mucositis, clin: oral cavity Muscle weakness: whole body

28 Continued ABVD (n=10) BEACOPP (n=1) ADVERSE EVENTS Musculo. Pain: back Musculo. Pain: bone Musculo. Pain: joint Musculo. Pain: limb Musculo. Pain: muscle Nail changes Nausea Neuro Pain: head/headache Neuropathy-motor Neuropathy-sensory Neutrophils Pain-other Platelets Pruritus Pulmonary-other Rigors/chills Sexual/Repro. Pain: urethra Supra Arrhyth: Sinus Tachy Sweating Taste alteration Thrombosis/embolism Vomiting Weight Loss MAX. GRADE ANY ADVERSE EVENT Response Two Initial Cycles of ABVD Followed by Response-adapted Therapy HIV-positive Patients Continued ABVD BEACOPP N % N % Complete Response Partial Response Total The LIFETEST Procedure Stratum 1: rowno = Initial ABVD APRIL 11-14, 2018 SWOG LYMPHOMA 28

29 100% Progression-Free Survival HIV-positive Patients 80% 60% 40% 20% 0% At Risk At Risk Failed 2-Year Estimate % At Risk Months After Registration 100% Stratum The LIFETEST 1: rowno = Procedure Initial ABVD Overall Survival HIV-positive Patients 80% 60% 40% 20% 0% At Risk At Risk Deaths 2-Year Estimate % At Risk Months After Registration APRIL 11-14, 2018 SWOG LYMPHOMA 29

30 S1608 Phase II Coordinating Group: SWOG Randomized Phase II Trial in Early Relapsing or Refractory Follicular Lymphoma Participants: SWOG, CTSU (Supported by Alliance, ECOG-ACRIN) Date Activated: 08/10/2017 Study Chairs: P Barr, B Link (Alliance), C Flowers (ECOG-ACRIN) Statisticians: H Li, M LeBlanc Data Coordinator: I Syquia SCHEMA R A N D O M I Z A T I O N TGR Obinutuzumab Lenalidomide + Obinutuzumab CHOP + Obinutuzumab Objectives To compare the complete response rate at 6 cycles after randomization as defined by centrally read PET/CT (integral biomarker) of two targeted therapeutic regimens (obinutuzumab + TGR-1202 or obinutuzumab + lenalidomide) with obinutuzumab + CHOP in patients with early relapsing or refractory follicular lymphoma. To validate the prognostic association of the m7- FLIPI model, demonstrating that the population of follicular lymphoma patients who respond poorly to chemoimmunotherapy are enriched for having a high-risk m7-flipi score, and that the score is associated with progression-free survival (integrated biomarker). To estimate the 30 month sustained complete response rate (CR30) defined by centrally read PET/CT with each of the regimens in this early relapsing or refractory follicular lymphoma population. APRIL 11-14, 2018 SWOG LYMPHOMA 30 S1608/II

31 To estimate best response at 12 cycles of therapy, progression-free survival, duration of response, and overall survival with each of the combinations in early relapsing or refractory follicular lymphoma. To evaluate the adverse effects of each of the regimens in early relapsing or refractory follicular lymphoma. To evaluate the predictive performance of noninvasive genotyping (m7-flipi in circulating tumor DNA) of plasma at study entry relative to standard tumor genotyping (m7-flipi) of formalin-fixed paraffin-embedded tumor tissue. To evaluate the association between the detection of active lymphoma by PET/CT and the detection of circulating tumor DNA in plasma at baseline, after 6 and 12 cycles, and at 30 months after initiation of study therapy Patient Population Patients must have follicular lymphoma ( I, II or IIIa) confirmed at initial diagnosis and at relapse with identifiable FDG avid disease on PET/CT. Patients must not have involvement with large cell lymphoma. Patients must have either failed to achieve a complete remission, or must have relapsed within two years after completing first line of bendamustine-containing chemoimmunotherapy. Patients must have the components of Follicular Lymphoma International Prognostic Index (FLIPI) available from diagnosis and at time of registration. Additionally, patients must have beta-2- microglobulin collected at time of registration. Patients must not have clinical evidence of central nervous system involvement by lymphoma. Patients must have received at least three cycles of bendamustine as first line therapy. Patients may have additionally received maintenance anti-cd-20 antibody based therapy or consolidative radioimmunotherapy within two years of the last dose of the bendamustine therapy. Patients must have completed systemic therapy at least 21 days prior to registration or completed radio/mmunotherapy at least 84 days prior to registration. Patients must have recovered from all treatment related toxicities prior to registration. Patients must not have had prior anthracycline based therapy, or any prior treatment with any PI3K inhibitor or lenalidomide. Relapsed patients must not have received any intervening chemotherapy. Patients must be able and willing to take prophylaxis as listed in the protocol. Patients must be at least 18 years of age and have a Zubrod performance status of 0-2. Patients must have adequate renal, hepatic, cardiac and hematologic function. Patients with Hepatitis B virus infection, or Hepatitis C virus infection, or known HIV infection are eligible with restrictions. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 miu/ml within days prior to registration. Stratification/Descriptive Factors Patient randomization will be stratified according to the following factors: (1) previous receipt of maintenance therapy: yes vs no; and (2) refractory status: lack of CR after completing first line bendamustine-containing chemoimmunotherapy vs disease relapse within two years of completing first line bendamustine-containing chemoimmunotherapy. If patients meet the definition of both refractory and relapsing within two years, they will be grouped with the refractory cohort. Accrual Goals The accrual goal for this study is 150 patients to achieve 135 eligible patients. Interim analyses are planned after response data for six cycles of treatment are available for half of patients on each arm. Summary Statement The trial opened to accrual on August 10, As of February 1, 2018, two patients had been registered to this study, one from Cancer Research Consortium of West Michigan and another from Washington University School of Medicine. APRIL 11-14, 2018 SWOG LYMPHOMA 31 S1608/II

32 EAY131 Master Protocol / Phase II Coordinating Group: ECOG-ACRIN NCI-MATCH: Molecular Analysis for Therapy Choice Participants: ECOG-ACRIN, CTSU Date Activated: 08/12/2015 Study Chairs: K Flaherty (ECOG-ACRIN), B Conley (NCI), P O'Dwyer (ECOG-ACRIN), A Chen (NCI), V Villalobos (SWOG) Molecular Profiling by Outside Lab SCHEMA Treatment for Molecular Profile of Interest Toxicity or Progression *As of May 1, 2017, patients must be screened via one of the outside laboratories listed in the protocol and only those patients with an applicable rare variant mutation of interest are eligible for subprotocol enrollment. Objectives To evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers/lymphomas/ multiple myeloma. To evaluate the proportion of patients alive and progression free at six months of treatment with targeted study agent in patients with advanced refractory cancers/lymphomas/multiple myeloma. To evaluate the time until death or disease progression. To identify potential predictive biomarkers beyond the genomic alteration by which treatment is assigned or resistance mechanisms using additional genomic, RNA, protein and imaging-based assessment platforms. To assess whether radiomic phenotypes obtained from pre-treatment imaging and changes from pre- through post-therapy imaging can predict Objective Response and Progression Free Survival and to evaluate the association between pre-treatment radiomic phenotypes and targeted gene mutation patterns of tumor biopsy specimens. Patient Population Patients must have histologically documented solid tumors or histologically confirmed diagnosis of lymphoma or multiple myeloma that has progressed following at least one line of standard systemic therapy and/or for whose disease no standard treatment exists that has been shown to prolong survival. Patients must have measurable disease and meet one of the criteria in the protocol regarding tissue procurement. Patients must not currently be receiving any other investigational agents. Any prior therapy, radiotherapy (except palliative radiation therapy of 30 Gy or less), or major surgery must have been completed at least four weeks prior to treatment on APRIL 11-14, 2018 SWOG LYMPHOMA 32 EAY131

33 NCI-MATCH and all adverse events due to prior therapy must have resolved to a 1 or better (except alopecia and lymphopenia) by start of treatment. Palliative radiation therapy must have been completed at least two weeks prior to start of treatment. Patients with brain metastases or primary brain tumors must have completed treatment, surgery, or radiation therapy at least four weeks prior to start of treatment. Patients must have discontinued steroids at least one week prior to registration and remain off steroids thereafter, except as permitted in the protocol. Patients with glioblastoma must have been on a stable dose of steroids, or be off steroids, for one week prior to registration to treatment step. Patients must not require the use of full dose coumarinderivative anticoagulants. Low molecular weight heparin is permitted for prophylactic or therapeutic use. Factor X inhibitors are permitted. Patients may receive non-protocol treatment after biopsy (if clinically indicated) until they receive notification of results, but patients may not enroll in another investigational study during this time and the therapy cannot be an arm in this trial. Patients must be at least 18 years of age, have an ECOG performance status of 0 or 1, must have a life expectancy of at least 3 months, and must be able to swallow tablets. Patients must have adequate hematologic, hepatic, renal, cardiac and marrow function. Patients must not have any uncontrolled intercurrent illness. HIV-positive patients are eligible provided they meet protocol criteria. Each subprotocol will have additional eligibility criteria that will be outlined in Section 2.0 of the agentspecific subprotocol. Only sites utilizing the CIRB as their IRB of record are able to participate in the trial. Accrual Goals The target screening accrual for this study is approximately 6,452 patients, with the goal of accruing 35 patients in each treatment subprotocol. If after screening 500 patients the total number of patients with actionable tumor alteration (therefore qualifying for treatment) is below 50, results will be presented to the steering committee for consideration of trial termination. Within any given subprotocol, if rate of enrollment is such that it is unlikely accrual can reach 25 patients by the time the overall study screening accrual goal is met, and if 13 patients have been treated and no responses have been observed, then the steering committee may consider terminating accrual in that subgroup due to lack of feasibility. After 500 patients are screened, the study design will be reassessed to assure its appropriateness. An interim analysis of the assay results will be performed after biopsies from approximately the first 200 patients are processed. Summary Statement As of May 15, 2017, biopsy material is no longer accepted for testing by a MATCH trial laboratory. Patients must now be screened via one of the outside laboratories listed in the protocol and only those patients with an applicable rare variant mutation of interest are eligible for a molecularly guided subprotocol. See the CTSU website for the list of subprotocols currently enrolling patients. ECOG-ACRIN reported a total of 6,482 screened patients and 743 patients enrolled for treatment as of December 31, This includes 891 screened and 102 molecularly matched SWOG registrations. See the Early Therapeutics & Rare Cancers chapter for the most recent summary from ECOG-ACRIN. APRIL 11-14, 2018 SWOG LYMPHOMA 33 EAY131