Validation and revision of the RANO Leptomeningeal Metastasis Group scorecard for response assessment.

e13546 Background: The Response Assessment in Neuro-Oncology (RANO) group has proposed a scorecard to evaluate response assessed by magnetic resonance imaging (MRI) during treatment of leptomeningeal metastasis (LM). Methods: To validate the LM-RANO scorecard, cerebrospinal MRI of 22 patients with LM from solid tumors were rated by 10 neuro-oncologists and 9 neuroradiologists at baseline and during follow-up after treatment. The original scorecard and its instructions were sent to the raters. The inter-observer agreement for the evaluation of single items was assessed using the Krippendorff alpha coefficient. The agreement between numerical parameters including scores at baseline and at follow-up after treatment and total scores was determined using the intraclass coefficient of correlation (ICC). Results: Instructions of the scorecard were not clear for the majority of raters. The alpha concordance coefficients obtained for the rating of single items at baseline and at follow-up were low (Krippendorf alpha coefficient < 0.61 for all raters). The best concordances were noted for spinal nodules (0.60). The worst concordances were obtained for brain linear leptomeningeal enhancement and cranial nerve enhancement. The concordance was better among neuroradiologists than among neuro-oncologists. A poor agreement was also noted when evaluating changes between baseline and follow-up and for total scores (ICC < 0.65 for the best score for all raters). Conclusions: Assessing response of LM by MRI remains challenging. The definition of a measurable lesion and the determination of response were the most important challenges. A central review is therefore recommended for clinical trials in LM. Based on this study we propose a new scorecard that will require a similar assessment as conducted here.

“CHARTA”: FOLFOX/Bevacizumab vs. FOLFOXIRI/Bevacizumab in advanced colorectal cancer—Final results, prognostic and potentially predictive factors from the randomized Phase II trial of the AIO.

3533 Background: FOLFOXIRI/Bevacizumab (Bev) is superior to FOLFIRI/Bev in the TRIBE trial (F Loupakis, NEJM 2014). The CHARTA trial was developed parallel to TRIBE with the same 4-drug-protocol but vs. FOLFOX/B ev as control arm. Methods: From 7/11 to 12/14 250 patients were randomized, including ECOG 0-2, ≥ 1 measurable lesion > 1cm, stratified by ESMO-Group 1,2,3 (HJ Schmoll, Ann Oncol 2012). Induction: 6 months, maintenance Capecitabine+Bev until progression or max.12 months, at P reinduction by investigators decision. 25% dose reduction was allowed in cycle 1 + 2 on the investigator’s discretion. Primary EP: significant improvement of PFS-rate @ 9 months (p<0.1, 2-sided Fisher’s-exact test); secondary EP: RR, PFS, OS, toxicity. Results: 241 pts. (1 not elig., 8 prot. violation) are evaluable after a follow up of 31.4 (0.1-51) months. m/f: 65%/35%, age 61y (21-82), ECOG 0-1/2: 96%/4%. The Primary Endpoint was met: PFS @ 9 months 56% vs. 68%, p= 0.086. PFS was improved: 9.8 vs. 12.0 months, HR 0.7 (ns.), identical to TRIBE with 9.7 vs. 12.1 months. Response rate (A/B): CR: 5%/5%, CR/PR 60%/70%, SD 25%/21%, PD 14%/9%. Final OS will be available at the meeting. Toxicity was low to moderate without major differences except ° ¾ diarrhea (12%/16%) and neutrophils (14%/20%). Clinical/molecular prognostic or predictive factors are equally distributed (stratification by ESMO groups) (see table). There are major, but mostly not significant differences in RR/ PFS in most subgroups, however, not strong enough to safely identify patients with high potential to benefit from the 4-drug combination. Therefore, a multivariate analysis to model a common prognostic and predictive risk score is ongoing and will be presented at the meeting. Conclusion: “CHARTA” supports the superiority of FOLFOXIRI/Bev. A combined prognostic and predictive classification is required to better select those patients with most potential benefit from the 4-drug combination. Clinical trial information: NCT01321957. [Table: see text]

Phase 1 study of the safety and efficacy of INCB050465 combined with obinutuzumab and bendamustine for relapsed or refractory (R/R) follicular lymphoma (FL) (CITADEL-102).

TPS7578 Background: Aberrant PI3Kδ activation is implicated in B-cell non-Hodgkin lymphomas (NHL) including FL, the most common indolent subtype. INCB050465, a selective PI3Kδ inhibitor, is being evaluated in an ongoing phase 1/2 study as monotherapy for r/r B-cell NHL, including FL (ASH 2016; Abstract 4195). Obinutuzumab plus bendamustine is approved for patients (pts) with rituximab-refractory FL. This phase 1 cohort expansion study will assess the safety, efficacy, and pharmacokinetics of INCB050465 combined with obinutuzumab and bendamustine in pts with r/r FL (NCT03039114). Methods: Eligible adults will have documented CD20+ FL r/r to 1–4 prior treatments (must include rituximab), ≥1 measurable lesion ( > 1.5 cm in ≥1 dimension), ECOG PS ≤2, and adequate hematologic, hepatic and renal function. Exclusion criteria will include: transformation of FL to aggressive lymphoma or receipt of allogeneic stem cell transplant (SCT) ≤6 months (or having graft-versus-host-disease after allogeneic or autologous SCT ≤3 months) before study start; receipt of any PI3K inhibitor, obinutuzumab, or bendamustine ≤12 months, or rituximab ≤1 month prior to study. Part 1 (safety run-in) will use a 3+3 design. Pts will receive INCB050465 PO at a dose of 20 mg QD continuously for 2 cycles (1 cycle = 4 wks) followed by 20 mg QW. Up to 2 dose reductions will be allowed. Pts will receive obinutuzumab 1000 mg IV (cycle 1: days 1, 8, and 15; cycles 2–6: day 1) and bendamustine 90 mg/m2 IV (cycles 1–6: days 1 and 2). In part 2 (expansion), the safety and efficacy of INCB050465 (maximum tolerated dose) plus obinutuzumab and bendamustine will be evaluated in 30 pts, including pts treated in part 1 at the dose level deemed safe and tolerated. In both parts 1 and 2, pts not progressing after 6 cycles will be maintained on INCB050465 at the dose deemed safe and tolerated, and will continue on obinutuzumab 1000 mg IV administered on Day 1 of every second cycle for an additional 24 cycles or until disease progression. Response will be assessed using Lugano criteria (FDG-PET; CT/MRI) every 12 wks until cycle 12 and every 16 wks thereafter. The trial is open for enrollment. Clinical trial information: NCT03039114.

Safety and efficacy during first line with cetuximab in KRAS wild-type metastatic colorectal cancer (mCRC): Results of a large prospective multicenter cohort carried out by the premium French observational study.

555 Background: Cetuximab improves benefit in patients with kras wild type when added to CT for mCRC (Crystal, opus, celim trials). In order to assess the safety and efficacy of cetuximab in daily-practices a national prospective observational multicenter study was performed. Methods: Physicians (n=94), in health institutions (44 public and 46 private hospitals, 4 cancer centers) enrolled prospectively 502 patients. The eligibility criteria were kras wild type mCRC treated with cetuximab in combination with CT as first-line regimen and at least one measurable lesion. Data are available at 3 months, for 496 patients enrolled between september 2009 to march 2012. Results: Mean age 65,7 years old, 62.9% male, ECOG score 0-1 88.1%, 2-3 11.9%, metastases site were liver 70%, lung 26% and others unlimited 39%. Resectable mCCR 10.6%, potentially resectable metastases 33.9% and unresectable 55.5%. Primary tumor location colon: right 20.9%, transverse 6%, left 35.3%, rectum 30.5%, others 7.3%. Primary cancer was resected in 66 % (n=332), 25% (n=125) received adjuvant CT. Cetuximab was administrated respectively every week(20.2%) or two weeks (79.8% of patients). CT regimens were folfiri 51.8%, folfox 4 36.5%, others 11.7%. At 3 months response rate was complete in 4.6%, partial 44.9%, stable 34%, progression disease 16.5%. Reasons for specific cetuximab treatment discontinuation (n=207) were progressive disease 35.3%, therapeutic break 23.2%, all grade cutaneous toxicity and allergic reaction 15.9%, patient request 2.9%, surgery recruitment 20% radiotherapy, radiofrequency and others 2.7%. Adverse events in grade 2 and 3-4 were respectively neutropenia (9.4%;7.9%), anemia (8.5%;1.4%), thrombocytopenia (2.6%;1%), diarrhea (10.8%;5.3%) vomiting (5.3%;2.2%), folliculitis (17.9%;3%), xerosis (13.3%;2%), paronychia (5%;0.9%), allergy 3.4%. Conclusions: Values reported are consistent with those previously identified trials and can better understand the reasons of drug stopping. The study continues to evaluate prognostic factors influencing response, toxicity and drug discontinuation.

A phase ll study of trastuzumab in combination with triweekly S-1 plus CDDP in HER2-positive advanced gastric cancer (HERBIS-1).

70 Background: S-1, an oral fluoropyrimidine, plus cisplatin (SP) regimen is one of the standard chemotherapy as first-line for advanced gastric cancer (AGC). Although ToGA study demonstrated that trastuzumab (T-mab) in combination with capecitabine plus cisplatin or fluorouracil plus cisplatin improved the overall survival of patients (pts) with HER2-positive AGC, there was no study evaluating the efficacy and the safety of T-mab in combination with SP regimen. Methods: Eligibility criteria included gastric or esophagogastric junction adenocarcinoma; HER2-positive confirmed by IHC and/or FISH (IHC 3+ or IHC 2+ and FISH positive); unresectable or recurrent; measurable lesion; no history of chemotherapy or radiotherapy; age≤75; ECOG PS of 0-1; and adequate organ function. Pts received S-1 at 40–60 mg depending on body surface area, po bid, day 1-14, and cisplatin 60 mg/m2, iv, day 1, plus T-mab 8 mg/ kg, iv, day 1 (6 mg/ kg, iv, d1 from 2nd course), repeated every 3 weeks until disease progression. Primary endpoint was response rate assessed by the RECIST (ver 1.1). The planned sample size was 50 based on the threshold response rate of 35%, the expected rate of 50%, power of 80%, and 1-sided α of 0.1. Results: A total of 56 pts were enrolled from July 2011 to May 2012. Two pts were ineligible with inadequate renal function and no measurable lesion. Characteristics of 54 eligible pts were as follows: median age of 66 (range 34-75), M/F: 42/12, PS0/1: 42/12, unresectable/recuurent: 51/3, and IHC 2+/3+: 9/45. As one patient did not receive the protocol treatment due to the rapid progression of tumor, the efficacy and the safety analyses were conducted in the full analysis set of 53 pts. The confirmed response rate assessed by the independent review committee was 68%, and the disease control rate was 94%. The response rate without interval confirmation was 75%. The grade 3/4 adverse events (>5% of pts) were as follows: neutropenia 30%, leucopenia 8%, anorexia 21%, diarrhea 8%, hypoalbuminemia 8%, vomiting 6%, and increased creatinine 6%. Conclusions: T-mab in combination with triweekly SP regimen showed promising antitumor activity and manageable toxicities in pts with HER2-positiveAGC. Clinical trial information: UMIN000005739.

Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin lymphoma (NHL)

10000 Background: Pediatric mature B-cell NHL differ from aggressive B-NHL of adults in terms of biology and treatment outcome. In contrast to adults, rituximab (Rx) is not established in the treatment of pediatric B-NHL has not be determined yet. Even the activity of Rx in pediatric B-NHL is not determined. We conducted a phase II window study to examine the activity of Rx in newly diagnosed pediatric B-NHL. Methods: Eligibility: age < 19 y, CD20 + B-NHL, ≥ 1 measurable lesion/s, informed consent. Exclusion: Lansky performance scale 5, pre-treatment, impaired renal-, heart-, liver-function, hepatitis B, pre-existing disease, pregnancy. Treatment: Rx 375 mg/m2 IV at day 1; concomitant therapy: Rasburicase, steroids only for anaphylaxis, intrathecal (IT) triple drug at days 1, 3 for CNS+ pts only. Begin of chemotherapy at day 5. Response evaluation: product of 2 perpendicular diameters of 1 - 3 index lesions/% blasts in BM/PB within 24 h prior to Rx and at day 5: responder (RP): at least 1 lesion with at least objective effect (decrease of ≥25%) and no progress (increase of ≥25 %) at other sites. Study plan: Simon 2-stage phase II with α and β = 5%. Response rate (RR) for poor activity was set to 45%, for good activity 65%. 33 pts entered the first stage, final evaluation after 79 pts. Results: One hundred thirty-six pts were enrolled from 04/04–08/08. NTC °3/4 toxicities: general condition 16%, fatigue 13%, anaphylaxis (chill/fever/bronchospasm) 6 (1/2/4)%, infection 3%, S-GOT/GPT 10%, acute tumor lysis (ATL) 7%, capillary leakage (0), toxic death (0). Forty-nine pts were not evaluable for response: Withdrawal (anaphylaxis 8, ATL 2, suspected progression, not verified 4, other 2), IT therapy in CNS- pts (8), corticosteroids (3), technical inadequacy of response evaluation (21), no index lesion (1). Of the 87 evaluable pts 37 were RPs (42.5%, 95%-CI 32% - 54%). RR by histology: BL/B-ALL 29/68, DLBCL 6/14, juvenile follicular lymphoma 1/2, PMBCL 1/1, B-NHL nfs 0/2. Fifty pts were non-RPs. Conclusions: Although the RR was lower than requested Rx as single agent is active in pediatric B-NHL. No significant financial relationships to disclose.

Validity of the modified RECIST criteria and EORTC PET criteria evaluated based on the pathologic findings for patients with resectable malignant pleural mesothelioma

e11639 Background: The unique growth pattern of malignant pleural mesothelioma (MPM) presents challenges for clinical investigators evaluating the responses to chemotherapy, which is an important surrogate endpoint for patient benefit, particularly in clinical trials. In patients with resectable MPM, multicenter clinical trials of neoadjuvant chemotherapy followed by extrapleral pneumonectomy (EPP) and subsequent radiotherapy have been attempted around the world. The applicability of modified RECIST based on the findings on CT images and EORTC (European Organization for Research and Treatment of Cancer) criteria based on the findings on FDG-PET images to resectable MPM would be challenging and significant, but their validity has never been examined. Methods: Between May 2006 and November 2008, 13 consecutive patients with resectable pathologically proven MPM were included in this study. All were initially treated with combination chemotherapy including cisplatin. EPP was successfully performed in all the patients. In addition to modified RECIST (CR vs PR vs SD vs PD), FDG uptake by the tumor on PET was also evaluated according to the EORTC PET criteria (CMR vs PMR vs SMD vs PMD). Also, pathologic findings (NT; no viable tumor vs MR; minimal residual vs GR; gross residual) were reviewed. Results: According to modified RECIST, in which the definition of measurable lesions is ≥10mm in diameter, 7 of the 13 patients investigated had no measurable lesion. Even when the definition of measurable lesions was changed to ≥5mm, 2 patients had no measurable lesion and 4 had only one lesion. In regard to the response, 4 of 11 patients with any measurable lesions were classified as PR, and 7 were classified as SD, while 8 patients were classified as PMR and 3 were classified as SMD according to the PET findings. Eight patients were classified as GR and 5 as MR. Kappa statistics suggested potential variation between the CT response and the pathologic findings (κ=0.214, 95% CI=-0.377 ∼ 0.806) and between the PET response and the pathologic findings (κ=0.286, 95% CI=-0.049 ∼ 0.620). Conclusions: Our data raise doubts about the validity of applying the modified RECIST criteria as well as EORTC PET criteria to resectable MPM. No significant financial relationships to disclose.

What can we do for gastrointestinal cancer patients with poor performance status (PS)?

19629 Background: The prognosis of advanced gastrointestinal cancer patients, especially those with poor PS, is generally dismal. Needless to say, such patients are ineligible for participation in clinical studies. However, there are many patients with poor PS who wish to receive chemotherapy. Methods: From June 2000 to October 2006, a total of 508 patients with advanced cancer, including 304 gastrointestinal cancer patients, were treated by chemotherapy in our hospital. Of these, 110 gastrointestinal cancer patients (gastric=35, colorectal=30, pancreatic=26, biliary tract=11, esophageal=8) had poor PS (ECOG PS 3 = 68 patients, PS 4 = 42 patients). In 103 patients with at least one measurable lesion, a partial response according to RECIST criteria was obtained in 13 patients (12.6%). In 60 patients with ascites (47 patients), pleural effusion (25 patients), or both (12 patients), 11 of the patients (18.3%) achieved decreased fluid accumulation. A decline in tumor markers (>25%) was observed in 28 patients. Improvement in PS was seen in 13 patients (11.8%). As a result, 35 patients (31.8 %, including 9 patients with PS 4) achieved a tumor response, a decrease in accumulated fluid, or a decline in tumor markers, which resulted in a survival benefit compared to the other 75 patients without effect (6.4 months vs. 2.3 months, p<0.001). Alleviation of some symptoms was observed in 28 out of 98 symptomatic patients (30.4%). A better response and/or a decline in tumor markers significantly correlated with alleviation of symptoms (p<0.001). No treatment related death was seen. Conclusions: With regard to response rate, chemotherapy was rarely effective for patients with advanced gastrointestinal cancer with poor PS. However, more than a few patients gained a certain survival benefit and alleviation of symptoms. Thus, chemotherapy may be warranted in cases of patients with advanced gastrointestinal cancer who wish to receive chemotherapy despite the low possibility of response. No significant financial relationships to disclose.