scholarly journals Lenalidomide Consolidation Added to Rituximab Maintenance Therapy in Patients Remaining PET Positive after Treatment for Relapsed Follicular Lymphoma: Phase 2 Australasian Leukaemia & Lymphoma Group NHL26 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2428-2428
Author(s):  
Judith Trotman ◽  
Peter Presgrave ◽  
Duncan P. Carradice ◽  
Douglas Stuart Lenton ◽  
Maher Gandhi ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Primary Endpoint ◽  
Conversion Rate ◽  
Research Funding ◽  
Type I ◽  
Phase 2 ◽  
Multicentre Phase ◽  
Rituximab Maintenance ◽  
Conversion Rates ◽  
Histological Transformation

Abstract Introduction The combination of rituximab & lenalidomide (R 2) is an established regimen for treatment of follicular lymphoma (FL), with efficacy reported in the first line and relapsed setting (Morchhauser NEJM 2018, Leonard JCO 2019). The inferior OS of patients who remain post-induction PET-CT positive (PET+ve) has also been demonstrated in both settings (Trotman Lancet Haem 2014, Lancet Oncol 2018, Ysebaert, ASH 2011). We sought to study the effect of R 2 in relapsed FL by examining its ability to convert to PET-negative (PET-ve) those patients who remain PET+ve after reinduction rituximab-chemotherapy. Methods This was a prospective, multicentre, Phase 2 study of patients with bulky Stage II, or Stage III-IV relapsed FL. Eligibility criteria were: at least stable disease on CT within 4-6 weeks of last cycle of re-induction rituximab-chemotherapy; ECOG ≤2; CrCL ³30mL/min; haemoglobin >80g/L, neutrophils >1.0 & platelets >75 x 10 9/L. Exclusion criteria were: histological transformation ≤12 months (mo); any interim-PET that was negative, and other malignancy ≤5 years. After enrolment pts underwent a centrally-reviewed PET within 8 weeks of D1 last cycle of re-induction rituximab-chemotherapy. Given the higher probability of further progression in the relapsed setting PET+ve was defined as a Deauville score (DS) 3-5. PET-ve patients were assigned rituximab maintenance q2mo for 2 years, and those remaining PET+ve were assigned R 2 to commence within 12 weeks. Lenalidomide schedule for R 2 pts was 10mg/d x 21 q28d, with dose modifications for tolerance, over a planned 2 years. Repeat PET scans were scheduled at 6 & 12 mo after starting R 2. The primary endpoint was the rate of conversion from postinduction PET+ve to PET-ve in evaluable patients 6 mo after commencing lenalidomide. Evaluable patients were defined as those receiving >63 days of Lenalidomide. Sample size calculations used a one-sided exact test for proportions, assuming a conversion rate of ³50% as worthy of further evaluation and ≤20% as unacceptable. Thus 16 evaluable patients were required to have 80% power with type I error of 5%. Secondary endpoints were PET conversion rates by baseline DS in the PET+ve, the toxicity & deliverability of R 2, and PFS & OS in both the PET+ve & PET-ve populations. Results Thirty-seven patients (pts) were recruited from Nov 2013 to Jan 2021 when the study was closed due to poor recruitment attributed to competing studies. Median (med) age was 67yrs (36-83); 58% male, med 2 (range 2-11) prior therapies incl. the recent rituximab-chemotherapy; FLIPI low risk (21%), intermediate risk (12%) high risk (67%). Eighteen of 37 (48.6%) pts were postinduction PET+ve. Med follow-up was 38 mo (0.8 - 76.4): 32 mo (0.8 - 76.4) in PET+ve and 42 mo (6.7 - 73.8) in PET-neg. Of the 18 PET+ve pts one was ineligible for R 2 due to reactivation of hepatitis B; 3 were not evaluable having not received >63 doses of lenalidomide due to progressive disease (PD). Thus 14/18 (78%) PET+ve pts were evaluable, of whom 5/14 (36%; 95% CI 11% - 61%) became PET-ve at 6-mo, thus not excluding a PET conversion rate of <20%, (p=0.14). If we had obtained full recruitment both additional pts would have had to convert to PET-neg to meet the primary endpoint. PET conversion occurred in 4/6 evaluable pts with DS 3 and 1/8 with DS 5. PD occurred in 14 pts: 11/17 PET+ve and 3/19 PET-ve. Med PFS was 30.8 mo (5.7-37.6) in the PET+ve and NR (95% CI 42.3-NR) in the PET-ve, p = 0.0001. Death occurred in 11/37 (30%): 7 from lymphoma (5 PET+ve), 1 other malignancy, 2 pneumonia, 1 aspergillosis. Med OS was 68.1 mo (9.6 - NR) in PET+ve and NR (95% CI 42.3 - NR) in PET-ve (p 0.059). Of the 17 PET+ve pts starting lenalidomide, deliverability was limited by both disease progression and AEs: 3 failed to receive 3 cycles, 6 pts received 4-6, and 8 pts 7-24 cycles. Mean number of lenalidomide doses was 213 (SD 188). At least one AE was reported in 16/17 (94%), most commonly neutropenia (n=10, 59%, Gd4 24%). At least one SAE occurred in 9/17 (53%): infections 2, malignancy 2, cardiac disorders 2, musculoskeletal 2, other causes 3 pts. Conclusion The high PET+ve rate of 49% (DS 3-5) after rituximab-chemotherapy for relapsed FL suggests the need for consolidation therapy. However, R 2 did not achieve a sufficiently high PET-conversion rate to justify further study. The inferior outcome of patients who remain PET+ve after treatment of relapse highlights the importance of investigating novel approaches in this setting. Figure 1 Figure 1. Disclosures Trotman: TAKEDA: Research Funding; beigene: Research Funding; roche: Research Funding; BMS: Research Funding; PCYC: Research Funding; JANSSEN: Research Funding. Gandhi: janssen: Research Funding; novartis: Honoraria. Butcher: WriteSource: Current Employment, Other: Medical writing for Pharma companies. Not pertinent to this abstract for which author is study Statisticiam.

scholarly journals Short Course of Bendamustine and Rituximab Followed By 90Y-Ibritumomab Tiuxetan in Patients with Chemotherapy-Naïve Follicular Lymphoma: Results of Fol-Brite

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1733-1733
Author(s):  
Frederick Lansigan ◽  
Bassem I Zaki ◽  
Stephanie P Yen ◽  
Eric S Winer ◽  
Helen Ryan ◽  
...  
Keyword(s):  
Partial Response ◽  
Follicular Lymphoma ◽  
Primary Endpoint ◽  
Conversion Rate ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Myelogenous Leukemia ◽  
Grade 3 ◽  
To Receive

Abstract Background: Y90 Ibritumumab tiuxetan (90YIT) is approved for use for follicular lymphoma (FL) patients (pts) who have achieved a complete or partial response to frontline chemotherapy; however, its use after bendamustine and rituximab (BR) has never been studied. BR has proven to be a superior frontline therapy over R-CHOP in the treatment of FL and is a widely used initial treatment strategy. In this prospective, single-arm, open-label, multicenter phase II trial, we assessed the response rate and safety of a short induction course of BR for 4 cycles followed by consolidation with 90YIT for chemotherapy-naïve pts with FL. Methods: Consenting pts greater than 18 years with chemotherapy naïve FL (grade 1-2 and 3a) requiring treatment were eligible for this study. All pts had Stage II-IV disease and had adequate hematologic, liver, and renal function. Treatment consisted of an initial dose of rituximab 375mg/m2. One week later, bendamustine 90mg/m2 was administered on days 1 and 2, and rituximab 375mg/m2 was given on day 1. BR was given for 4 cycles every 28 days. Pts were restaged 4-6 weeks after the last dose of BR. Pts were considered eligible for consolidation with 90YIT if they obtained at least a partial response after induction, had a platelet count greater than 100,000/mm3, a granulocyte count greater than 1,500/mm3, and bone marrow infiltration less than 25%. 90YIT was give 6-12 weeks after completion of the last cycle of BR. The primary endpoint of this study is complete and unconfirmed complete response (CR/CRu) rate after sequential therapy with BR followed by 90YIT. Secondary endpoints are overall response rate after 4 cycles of BR, conversion rate from partial response (PR) after BR to CR/CRu after 90YIT, progression-free survival, and safety. The 1999 NHL Working Group Criteria was used to assess response. Results: Forty-two pts were enrolled in this study: 38 pts initiated study treatment, and 4 were screen failures. Median age was 58 years [range 31-74]. The study enrolled FLIPI low (18%), intermediate (47%), high (34%) risk pts; 32 of 38 (84%) were Grade 1-2 and 6 (16%) were Grade 3a. Response rates after 4 cycles of BR: Thirty-eight pts have completed 4 cycles of BR and 38 are evaluable for response. Twenty-two of 38 evaluable pts achieved a CR/CRu (58%) and 15 of 38 pts had a PR (39%) for an overall response rate (ORR) of 97%. One pt had stable disease (SD). Response rates after BR followed by 90YIT: Thirty of 38 BR-treated pts have received 90YIT and are evaluable for the primary endpoint of CR/CRu. Of the 38 BR treated pts, two in CR were unable to receive 90YIT due low platelets, one was not eligible to receive 90YIT due to achievement of SD only, one declined treatment, and four are not yet evaluable for response. Twenty-five of 30 evaluable pts are in CR/CRu (83%), 4 remain in PR (13%) after 90YIT and one progressed during 90YIT, for an ORR of 96%. Of the 14 pts who had a PR after BR, 7 (50%) converted to a CR/CRu immediately after 90YIT, with three (21%) additional conversions to CR/CRu in follow-up, the latest occurring 16 months after 90YIT. Grade 3-4 hematologic toxicities during BR included: lymphopenia (36%), neutropenia (8%), thrombocytopenia (3%), leukopenia (3%). Non-hematologic toxicities included grade 2 phlebitis (14%) and grade 3 hyperglycemia (8%), hyponatremia (3%), diarrhea (3%), infusion-related reaction (3%), headache (3%), rectal hemorrhage (3%). Grade 3-4 hematologic toxicities after 90YIT included: neutropenia (33%), leukopenia (36%), thrombocytopenia (36%), lymphopenia (14%), anemia (3%). Non-hematologic toxicities included skin infection (3%). Median neutrophil recovery was 8 weeks [range 8 to 12] and median platelet recovery was 9 weeks [range 5 to 36] after Y90IT. There have been no incidences of neutropenic fever. One pt developed chronic myelogenous leukemia, occurring 11 months after treatment with BR followed by Y90-IT. There have been no cases of myelodysplasia or acute myelogenous leukemia. Conclusions: In this nearly final analysis, the CR/CRu rate of pts completing all study therapy (BR followed by 90YIT) is 83%, the ORR is 96%, and the conversion rate from PR to CR/CRu is 71%. We conclude that sequential treatment with BR followed by Y90IT is highly effective and safe, and should be considered as a frontline treatment option for FL. Disclosures Lansigan: Teva Pharmaceuticals: Research Funding; Spectrum Pharmaceuticals: Research Funding.

Rituximab Plus Lenalidomide Improves the Complete Remission Rate in Comparison with Rituximab Monotherapy in Untreated Follicular Lymphoma Patients in Need of Therapy. Primary Endpoint Analysis of the Randomized Phase-2 Trial SAKK 35/10

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 799-799 ◽  
Author(s):  
Eva Kimby ◽  
Giovanni Martinelli ◽  
Bjorn Ostenstad ◽  
Ulrich JM Mey ◽  
Daniel Rauch ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Primary Endpoint ◽  
Research Funding ◽  
Single Agent ◽  
Stage Iv ◽  
Phase 2 ◽  
Advisory Committees ◽  
Grade 3 ◽  
Intent To Treat

Abstract Background: Previous trials from the Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) showed that therapy with single-agent rituximab can produce long-term remissions in a sizeable subset of follicular lymphoma (FL) patients, with overall survival not inferior to chemo-immunotherapy, providing the rationale for the development of chemotherapy-free treatment strategies. Promising results have also been reported with the combination of rituximab and lenalidomide. The SAKK 35/10 phase-2 study was developed and conducted by the SAKK in cooperation with the NLG to compare the activity of rituximab plus lenalidomide versus single-agent rituximab in the first-line FL therapy. Methods: Patients with histologically confirmed untreated FL, grade 1, 2, 3a and in need of systemic therapy, were randomized either to rituximab monotherapy (R) (8 infusions of 375mg/m2 at day 1 of weeks 1, 2, 3, 4, and repeated at day 1 of weeks 12, 13, 14 and 15) or to rituximab (given at the same schedule) in combination with lenalidomide (RL) (lenalidomide given orally, 15 mg daily, starting 14 days before the first rituximab administration and continuously until 14 days after the last). The primary endpoint was the complete response (CR/CRu) assessed at week 23, defined according to the NCI standardized criteria (Cheson et al 1999). The study sample size was calculated to allow the detection of a 20% increase of the CR/CRu rate with RL over R, with 90% power and a type I error of 0.10. The 2 arms were compared using a one-sided Z-test with unpooled variance for proportions. Trial treatment was discontinued in patients who at week 10 did not achieve at least a minimal response, defined as reduction of more than 25% in the sum of product of tumor diameters (SPD), and rescue chemotherapy was given at the discretion of the treating physician. Results: In total, 154 patients were randomized; 77 (40 women and 37 men; median age 63yrs, range 29-85; 52% with stage IV and 47% with poor-risk FLIPI score) were allocated to arm R and 77 (42 women and 35 men; median age 61yrs, range 26-80; 48% with stage IV and 47% with poor-risk FLIPI score) to arm RL. Treatment was discontinued by 21 (28%) patients in arm R, in 16 due to lack of response at week 10 and in 1 due to toxicity, and by 19 (25%) patients in arm RL, in 3 due to lack of response at week 10 and in 13 due to toxicity. Adverse events of any grade were reported in 91% of patients in arm R and 100% in arm RL and adverse events of grade ≥3 were more common in arm RL than in arm R (51% vs 18% of patients). Grade 3-4 neutropenia was observed in 5% of patients in arm R and 19% in arm RL. The primary endpoint analysis (using the response assessment from the local investigators, reviewed by the study chairs) showed a significantly higher CR/CRu rate in patients treated with RL in comparison with those receiving R. This difference was observed both in the intent-to-treat (CR/CRu rate, 36% vs. 25%, respectively; p=0.056) and the per-protocol population (CR/CRu rate, 42% vs. 28%, respectively; p=0.049). Conclusions: The addition of lenalidomide to rituximab results in a significantly better CR/CRu at the cost of an expected increased toxicity. Further follow-up is needed to ascertain whether the response improvement will translate into prolonged time to next treatment and superior progression-free and overall survival rates. TableInvestigators’ assessment of the response at week 23 in the intent-to-treat (ITT) population Rituximab (N=77) Rituximab+Lenalidomide (N=77)Response category n (%)[95% C.I.]n (%)[95% C.I.]CR/CRu19 (25) [16-36%]28 (36)[26-48%] PR28 (36) [26-48%]35 (45)[34-57%]SD6 (8) [3-16%]4 (5)[1.4-13%]PD/relapse2 (3) [0.3-9%]3 (4)[0.8-11%]Not evaluable*22 (29) [19-40%]7 (9)[4-18%]*Patients with no assessment at week 23, including patients not achieving at least a minimal response at week 10. Disclosures Kimby: Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide, not approved for follicular lymphoma. Mey:Celgene: Membership on an entity's Board of Directors or advisory committees. Ferreri:Celgene: Research Funding. Bargetzi:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Krasniqi:Roche, Takeda: Membership on an entity's Board of Directors or advisory committees. Zucca:Roche, Mundivarma, Novartis: Consultancy, Honoraria, Research Funding.

Bortezomib In Combination with Rituximab, Cyclophosphamide, and Prednisone with or without Doxorubicin Followed by Rituximab Maintenance In Patients with Relapsed or Refractory Follicular Lymphoma: Results of a Phase 2 Study.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2798-2798 ◽  
Author(s):  
Michael Craig ◽  
Wahid T Hanna ◽  
Fernando Cabanillas ◽  
Chien-Shing Chen ◽  
Sudha Parasuraman ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Research Funding ◽  
Marginal Zone ◽  
Median Number ◽  
Marginal Zone Lymphoma ◽  
Phase 2 ◽  
Advisory Committees ◽  
Rituximab Maintenance ◽  
Grade 3

Abstract Abstract 2798 Background: Non-Hodgkin's lymphoma is the most common hematologic malignancy, with an estimated >65,000 new cases in the US in 2010. The indolent follicular lymphoma (FL) and marginal zone lymphoma (MZL) subtypes account for approximately 22% and 10% of cases, respectively. Rituximab, cyclophosphamide, vincristine, and prednisone, with doxorubicin (R-CHOP) or without (R-CVP) are the most common regimens used for frontline and relapsed/refractory FL. Bortezomib (VELCADE®) has shown activity alone and with rituximab in relapsed/refractory FL/MZL, and also in combination with chemo-immunotherapy regimens such as R-CHOP. However, overlapping peripheral neuropathy (PN) with vincristine may limit bortezomib dosing. Thus, the aim of this phase 2, two-arm, non-randomized, multicenter study was to evaluate the safety and efficacy of administering bortezomib in place of vincristine in the R-CHOP and R-CVP regimens. Methods: Patients aged ≥18 years with relapsed or refractory FL (including transformed FL) or MZL following ≥1 prior chemotherapy, ≥1 measurable tumor mass, ECOG performance status ≤2, no grade ≥2 residual toxicity from previous therapy/surgery, no grade ≥2 PN, and adequate hematologic, renal, and hepatic function were eligible. Based on investigator preference, patients received up to six 21-day cycles of bortezomib 1.6 mg/m2 IV on days 1 and 8, rituximab 375 mg/m2 IV on day 1, and prednisone 100 mg PO on days 1–5, plus either cyclophosphamide 1000 mg/m2 IV (VR-CP arm), or cyclophosphamide 750 mg/m2 IV and doxorubicin 50 mg/m2 IV (VR-CAP arm) on day 1. All patients then received rituximab 375 mg/m2 IV every 3 months for ≤2 years as maintenance. The primary endpoint was complete response (CR) rate, determined after all patients completed the 12-week follow-up visit. Secondary endpoints included overall response rate (ORR; CR + partial response [PR]), duration of response (DOR), progression-free survival (PFS), and safety/tolerability. Response was assessed by investigators using modified International Workshop Response Criteria. Toxicities were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Results: A total of 55 patients have been enrolled, 48 to VR-CP and 7 to VR-CAP; reasons for selecting VR-CP included extent of prior anthracycline therapy (56%), study center preference (25%), response to prior R-CVP (13%), and age (10%). Of the 48 VR-CP patients, 50% were male, 88% were white, median age was 63.5 years (range 40–85), 47 had FL (52/33/15% grade 1/2/3; 19/43/38% low/intermediate/high risk by FL International Prognostic Index [FLIPI]), and 1 had MZL. Median number of prior lines of therapy was 2 (range 1–10), which included R-CHOP in 27 (56%), rituximab in 19 (40%), and R-CVP in 7 (15%) patients. Of 47 evaluable patients, 14 (30%) achieved CR and 23 (49%; including 1 MZL) PR (ORR 79%). Median DOR and PFS have not been reached. Patients received a median of 6 (range 2–6) cycles of VR-CP; 40 (83%) received all 6 cycles, and 28 (58%) have continued into the rituximab maintenance phase. All patients reported ≥1 adverse event (AE), including 65% with grade ≥3 AEs, and 25% with serious AEs. Most common AEs included diarrhea (52%), nausea (46%), fatigue (44%), neutropenia (31%), constipation, and vomiting (each 23%); grade ≥3 AEs included neutropenia (27%), lymphopenia (10%), and thrombocytopenia (6%). The incidence of PN was 21% (2% grade ≥3). Four (8%) patients discontinued due to AEs. Of 7 VR-CAP patients (2 male, 7 white, median age 57 years [range 55–73]), 4 had FL (3 grade 1, 1 unknown; all FLIPI high-risk), 2 MZL, and 1 chronic lymphocytic leukemia. Median number of prior lines of therapy was 1 (range 1–8). Of 6 response-evaluable patients, 0/4 achieved CR/PR (3 FL, 1 MZL; ORR 67%). Five patients received all 6 cycles; 4 have continued into rituximab maintenance. AEs included fatigue (n=5), alopecia, neutropenia (each n=4), anemia, constipation, nausea, rigors, and thrombocytopenia (each n=3). Neutropenia (n=4) was the only grade ≥3 AE reported in >1 patient. PN was seen in 2 patients (no grade 3). Two patients had serious AEs. There have been no on-study deaths in either arm. Conclusion: These results indicate that VR-CP is active, with a 30% CR rate, in patients with relapsed or refractory FL/MZL, including those who had received prior chemo-immunotherapy. Prolonged follow-up is required to evaluate DOR and PFS; updated results will be presented. Disclosures: Craig: Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Use of bortezomib in combination in follicular lymphoma and marginal zone lymphoma. Cabanillas:Celgene: Consultancy, Research Funding; Bayer: Research Funding; Pfizer: Research Funding. Parasuraman:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. O'Connor:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Multinational, Open-Label Phase 2 Study Of Ruxolitinib In Asian Patients (Pts) With Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (PPV-MF), Or Post–Essential Thrombocythemia MF (PET-MF)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4086-4086
Author(s):  
Chul Won Jung ◽  
Lee-Yung Shih ◽  
Zhijian Xiao ◽  
Jie Jin ◽  
Hsin-An Hou ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Research Funding ◽  
Phase 2 ◽  
Spleen Volume ◽  
Open Label ◽  
Phase 3 ◽  
Phase 2 Study ◽  
Open Label Phase ◽  
Large Phase ◽  
Grade 3

Abstract Background Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated rapid and durable reductions in splenomegaly, improved MF-related symptoms and quality of life (QoL), and prolonged survival in 2 phase 3 studies comparing ruxolitinib with placebo (COMFORT-I) and best available therapy (COMFORT-II). However, no clinical trial in pts with MF had been conducted in Asian countries, and only a limited number of Asian pts or healthy volunteers had been enrolled in any ruxolitinib study. Methods This study was an open-label phase 2 study evaluating ruxolitinib in Asian pts with PMF, PPV-MF, or PET-MF who had palpable splenomegaly ≥ 5 cm below the costal margin and intermediate-2– or high-risk MF by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. Pts received starting doses of ruxolitinib 15 or 20 mg twice daily (bid) based on baseline platelet count (100-200 or > 200 × 109/L, respectively); dose adjustments balancing safety and efficacy were allowed to titrate each pt to their most appropriate dose. The primary endpoint was met if the proportion of pts achieving ≥ 35% reduction in spleen volume from baseline at week 24 was ≥ 27.5% as measured by MRI/CT. Symptomatic response was assessed as a secondary endpoint using the 7-day modified MF Symptom Assessment Form (MFSAF) v2.0 total symptom score (TSS) and European Organisation for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30). The study was conducted in China (n = 63), Japan (n = 30), Korea (n = 17), and Taiwan (n = 10). The data cutoff date for this analysis was 7 June 2013. Results Overall, 120 pts were enrolled (PMF, n = 80; PPV-MF, n = 21; PET-MF, n = 19), and their baseline characteristics were as follows: median age, 61 years (range, 25-80 years); 51.7% female; 69.2% intermediate-2 and 30.8% high risk by IWG-MRT criteria; median palpable spleen size, 15 cm (range, 5-45 cm); median spleen volume, 2159 cm3; 55.8% of pts had prior exposure to hydroxyurea. The median follow-up was 8.44 months; 22.5% of pts discontinued treatment, primarily for adverse events (AEs; 9.2%) and disease progression (7.5%). The median duration of treatment was 8.44 months (range, 0.5-21.7 months), and the median daily dose was 20.64 mg/day in the 15 mg bid group (n = 46) and 36.11 mg/day in the 20 mg bid group (n = 74). All pts were evaluable for achievement of the primary endpoint, 101 pts remained on study and were evaluable at week 24, and 96 pts had nonzero scores on the MFSAF-TSS and were evaluable for a reduction from baseline. Most pts who had assessments at week 24 (91% [92/101]) had a reduction from baseline in spleen volume (Figure). The study met the primary endpoint, with 31.7% (38/120) of all pts achieving ≥ 35% reduction from baseline at week 24. Overall, 38.3% (46/120) of pts achieved ≥ 35% reduction from baseline in spleen volume at any time on study. As measured by the 7-day MFSAF, 49% (47/96) of pts achieved ≥ 50% reduction from baseline in TSS (median reduction, 47.2%). Pts experienced an improvement from baseline at week 24 in EORTC global health status/QoL (mean change, 5.2). The most common nonhematologic AEs (≥ 10%) regardless of relationship to study medication included diarrhea (25.8%), upper respiratory tract infection (17.5%), ALT level increased (15.0%), pyrexia (15.0%), AST level increased (13.3%), cough (11.7%), herpes zoster infection (11.7%), nasopharyngitis (10.8%), constipation (10.0%), gamma-glutamyl transferase level increased (10.0%), and headache (10.0%), and most were grade 1/2. Serious AEs were reported for 24.2% of pts, and 65.8% of all pts had grade 3/4 AEs. The most common new or worsening laboratory abnormalities were low hemoglobin (all grade 3, 55.7%), low lymphocyte (grade 3/4, 19.5%), low platelet (grade 3/4, 15.3%), and low ANC (grade 3/4, 7.6%) levels. AEs observed in this study were consistent with those observed in the 2 large phase 3 COMFORT studies. Six pts (5%) died on treatment or within 30 days of discontinuation. Summary/conclusions Findings from this study demonstrated that ruxolitinib was relatively well tolerated in Asian pts with MF and provided substantial reductions in splenomegaly and modest improvements in MF-associated symptoms. The AEs observed with ruxolitinib treatment in this study are consistent with those observed in the large phase 3 COMFORT studies, and there were no new AEs associated with ruxolitinib in Asian pts with MF. Disclosures: Okamoto: Novartis: Honoraria, Research Funding. Sirulnik:Novartis: Employment. Ruiz:Novartis: Employment. Amagasaki:Novartis: Employment. Ito:Novartis: Employment. Akashi:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Rituximab Maintenance after Chemoimmunotherapy Induction in 1st and 2nd Line Improves Progression Free Survival: Planned Interim Analysis of the International Randomized AGMT-CLL8/a Mabtenance Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 20-20 ◽  
Author(s):  
Richard Greil ◽  
Petra Obrtlikova ◽  
Lukas Smolej ◽  
Tomas Kozak ◽  
Michael Steurer ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Interim Analysis ◽  
Research Funding ◽  
Alternative Hypothesis ◽  
Induction Treatment ◽  
P Value ◽  
Secondary Malignancies ◽  
Secondary Neoplasms ◽  
Rituximab Maintenance ◽  
Induction Regimen

Abstract Introduction: Chemoimmunotherapy has become a standard approach in previously untreated and also in pretreated CLL. Addition of Rituximab to FC in fit patients has proven superior to chemotherapy alone and more recently aCD20 treatment was shown to improve outcomes in patients treated with Chlorambucil, suggesting that immunotherapy may be of benefit, independent of the chosen chemotherapy backbone. In follicular and mantle cell lymphoma rituximab maintenance treatment has become a clinical standard. While we and others have presented Phase II data on the feasibility of Rituximab maintenance after chemoimmunotherapy induction, there are currently no available randomized data on the efficacy of such an approach. Study design: Patients were recruited after informed consent at the end of any Rituximab-containing induction treatment in 1st or 2nd line that achieved at least a PR. Excluded were patients with uncontrolled bacterial or viral infections and conditions that might severely affect life-expectancy (such as other malignancy, heart disease etc). The trial was registered at clinicaltrials.gov with the identifier NCT01118234. Randomization was stratified by country, line of treatment, induction response and type of induction regimen. Primary endpoint was PFS and a planned sample-size of 256 patients was calculated. All patients were recruited in participating centers between September 2009 and December 2013. An interim analysis was planned to be conducted after half of the planned events (i.e. 46) were observed and is presented here. Results: The current analysis includes 263 patients enrolled into the trial. Patients had a median age of 63 years, 28.9% were female and 80.6% were enrolled after 1st induction treatment. Hierarchical FISH cytogenetic risk was available in 221 patients: del17p 3.1%, del11q 27.6%, tris 12 10.8%, del13q 36.2%, and normal FISH karyotype 21.2%. IgVH Mutation state was available in 161 patients at time of interim analysis and 67% were unmutated. The induction regimen was FCR in 73.5% and BR in 20.2%, the response to induction treatment was CR/CRi in 58% and PR in 41.8% of patients and 57% scored negative in an 8-colour MRD flowcytometric analysis after induction. Rituximab treatment was allocated to 134 patients and 129 were in the observation arm. No significant imbalances in randomization were found in the above-mentioned parameters. Median observation time is currently 17.3 months. Regarding toxicities the current state of monitoring allows an analysis on the level of SAEs only. SAE causes were well balanced between arms with the exception of infectious SAEs - 32 in the rituximab and 22 in the observation arm, 3 deaths were attributed to infections (1 in the rituximab arm and 2 in the observation arm) - and secondary malignancies (8 in the rituximab arm vs. 1 in the observation arm). Four of the neoplasms in the rituximab arm were localized non-melanoma skin cancers and the 2 deaths from malignomas occurred one in each arm. Regarding efficacy, currently 27.9% have progressed in the observation arm and 14.9% in the rituximab arm. Ten patients died in the observation arm and 7 in the rituximab arm. The primary endpoint (PFS) is significantly in favour of rituximab maintenance (see Fig) with a p-value of 0.007 and a PFS at 17.3 months of 85.1% vs.75.5% in rituximab vs. observation arms, respectively. To account for toxicities and secondary neoplasms an EFS was calculated counting secondary malignancies, termination of treatment due to toxicities, progression or death as events. In this analysis the benefit was preserved, albeit with a lower p-value of 0.03. The observed benefit seemed independent from response after induction (CR vs. PR), but associated with positive MRD state after induction. Further factors that influenced the benefit in exploratory subgroup analyses were sex, cytogenetics, IgVH and B-symptoms at diagnosis. Conclusions: Rituximab maintenance after chemoimmunotherapy induction in CLL seems feasible, although with an increase in infectious complications, and shows signs of efficacy in this interim analysis. The presented interim analysis refutes the alternative hypothesis and allows the trial to continue. Exploratory analyses suggest that with longer follow-up it may be possible to define subpopulations with larger benefit from extended immunotherapy. Figure: PFS by treatment arm (Observation arm: …; Rituximab arm: __) Figure:. PFS by treatment arm (Observation arm: …; Rituximab arm: __) Disclosures Greil: Roche: Honoraria; Pfizer: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Astra-Zeneca: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; Janssen-Cilag: Honoraria; Merck: Honoraria; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Sanofi Aventis: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding. Off Label Use: Rituximab in Maintenace Treatment of CLL. Kozak:Roche: Honoraria, Travel grants Other. Girschikofsky:Pfizer: Honoraria, Research Funding; Mundipharm: Consultancy, Honoraria. Petzer:Celgene: Honoraria, unrestricted grant Other. Egle:Roche: Honoraria, Research Funding, Travel Grants Other.

Phase 2 Trial of Entospletinib (GS-9973), a Selective Syk Inhibitor, in Indolent Non-Hodgkin's Lymphoma (iNHL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1545-1545 ◽  
Author(s):  
Jeff P. Sharman ◽  
Leonard M. Klein ◽  
Michael Boxer ◽  
Kathryn S. Kolibaba ◽  
Steve Abella ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Median Duration ◽  
Research Funding ◽  
Alkylating Agents ◽  
Response Assessment ◽  
Baseline Risk ◽  
Phase 2 ◽  
Prognostic Features ◽  
Phase 2 Trial ◽  
First Response

Abstract Background: Spleen tyrosine kinase (Syk) is a mediator of B-cell receptor signaling in normal and transformed B-cells. Entospletinib is an orally bioavailable, selective inhibitor of Syk. Methods: This Phase 2 trial is evaluating entospletinib 800 mg BID in a study of 204 patients with previously treated lymphoid malignancies. Tumor imaging was planned at weeks 8, 16, 24 and then every 12. Tumor response was assessed per Cheson 2007 criteria. Results: A cohort of 69 patients with iNHL (41 follicular lymphoma [FL], 11 lymphoplasmacytoid lymphoma [LPL], 17 marginal zone lymphoma [MZL]) are included in this analysis. Median age was 66 years (range 41 - 89). 58% were male. The median number of prior treatments (Rxs) regimens was 3 (range 1- 14). Prior Rxs included anti-CD20 antibodies (rituximab 99%, ofatumumab 4%), alkylating agents (90%; bendamustine 51%) and anthracyclines (35%). Baseline risk factors: Ann Arbor Stg III-IV (70%), Gr 3a FL (29%), FLIPI ≥3 (34%). Median duration of Rx was 16 weeks with 10 patients continuing on Rx. Entospletinib was generally well tolerated. The most common TEAEs (any Grade/≥Gr 3, independent of causality) were fatigue (54%/13%), nausea (49%/4%), diarrhea(36%/0%), vomiting (26%/0%), headache (23%/1%), pyrexia (23%/3%), decreased appetite (22%/0%), constipation (22%/1%) and common laboratory abnormalities were increased AST (33%/15%), increased ALT (41%/19%), increased total bilirubin (32%/16%), anemia (36%/13%) and neutropenia (38%/13%). 4 patients died while on study from progressive disease. At the time of this analysis, 66 of 69 patients have been treated through first response assessment (1 patient ongoing not reaching first response assessment, 1 patient discontinued due to AE and 1 patient withdrew consent prior to it). 38 out of 61 (62%) patients evaluable for SPD experienced reduced tumor burden, with median duration of Rx 28 weeks (range 4-92). 9/61 (15%) achieved a decrease of ≥ 50% in SPD. The ORR was 13.0% (95% CI: 6.1%, 23.3%), with 7 patients achieving a PR, one LPL patient achieving MR and one patient achieving a CR. Forty-one patients (59.4%) had stable disease. The primary end point of 24 weeks PFS was 48.9% (95% CI: 34.6%, 61.7%). Median PFS was 5.5 months (95% CI: 4.4 months, 8.2 months). There were 39 patients (56.5%) with events of disease progression. Conclusions: Entospletinib monotherapy given with this dose and schedule was well tolerated and demonstrated activity in patients with advanced relapsed iNHL, including those with poor prognostic features. Further development of entospletinib in iNHL will focus on the development of combination approaches with chemotherapy and targeted agents. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Sharman: Calistoga: Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics, Inc.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Roche: Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Off Label Use: Management of CLL/SLL and follicular lymphoma. Kolibaba:Takeda Pharmaceuticals International Co.: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Janssen: Research Funding; GSK: Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding. Abella:Gilead: Employment. Eng:Gilead: Employment. He:Gilead Sciences: Employment. Hu:gilead: Employment. Yasenchak:Seattle Genetics, Inc.: Research Funding.

Randomized, double-blind, placebo-controlled, phase II trial of first-line platinum/docetaxel with or without erlotinib (E) in patients (pts) with recurrent and/or metastatic (R/M) head and neck squamous cell carcinomas (HNSCCs).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6017-6017 ◽  
Author(s):  
William Nassib William ◽  
Lei Feng ◽  
Merrill S. Kies ◽  
Salmaan Ahmed ◽  
George R. Blumenschein ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Type I Error ◽  
Performance Status ◽  
Local Treatment ◽  
Progression Free Survival ◽  
Type I ◽  
Phase 2 ◽  
First Line ◽  
Double Blind ◽  
Phase 2 Trial

6017 Background: In a single-arm, phase 2 study, we previously demonstrated that in pts with R/M HNSCC, cisplatin, docetaxel and E improved progression-free survival (PFS) compared to historical data (Kim et al., ASCO 2006). Herein, we evaluated this regimen in a single center, randomized, phase 2 trial. Methods: Pts with R/M HNSCC, with a performance status (PS) 0-2, were randomized (1:1) to receive up to 6 cycles of first-line chemotherapy with cisplatin 75 mg/m2 (or carboplatin AUC 6) and docetaxel 75 mg/m2 i.v. on day 1 every 21 days, plus placebo (P) vs. E 150 mg p.o. daily, followed by maintenance P or E until disease progression. The primary endpoint was PFS. With 120 pts, the study had 80% power to detect an improvement in median PFS from 3.0 to 4.9 months with a two-sided type I error rate of 0.1. Results: From 05/2010 to 07/2015, 120 pts were randomized to the P (N = 60) or E (N = 60) groups. All pts but one initiated treatment and were eligible for evaluation of the primary endpoint – 92 males; median age 62 years; 52 oropharynx, 40 oral cavity, 19 larynx, 8 hypopharynx cancer pts; 86 current/former smokers; 43 with recurrence within 6 months of completion of local treatment; 27 with prior exposure to EGFR inhibitors. Median PFS was 4.4 vs. 6.1 months for the P and E groups, respectively (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.42-0.95 months, p = 0.026). Response rates were 44% vs. 56% for P vs. E (p = 0.21). Median overall survival (OS) for P- and E-treated pts was 13.7 vs. 17.0 months (HR = 0.67, 95% CI 0.43-1.04, p = 0.07). Benefits from E on PFS and OS were more pronounced in pts with oropharyngeal tumors (p≤0.05 for interaction). In the E group, first-cycle rash grade 2-4 (34% pts) was associated with longer OS (HR = 0.40, p = 0.02). E-treated pts experienced a higher incidence of grade 3-4 adverse events (33.9 vs. 53.3%), including diarrhea (3 vs.17%), dehydration (5 vs. 15%), nausea (5 vs. 14%), rash (0 vs. 12%). Conclusions: This study met its primary endpoint. Addition of E to first-line platinum/docetaxel improved PFS and OS. This regimen may warrant further evaluation in randomized, phase 3 trials. Clinical trial information: NCT01064479.

scholarly journals Implication of Inherited Genetic Variants Associated with Follicular Lymphoma Susceptibility in the Prognosis of Patients Treated By Immunochemotherapy in PRIMA Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2780-2780
Author(s):  
Herve Ghesquieres ◽  
Youenn Drouet ◽  
Sarah Huet ◽  
Guillaume Cartron ◽  
Marie-Helene Delfau ◽  
...  
Keyword(s):  
At Risk ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Advisory Committees ◽  
Cox Models ◽  
Rituximab Maintenance ◽  
Genome Wide ◽  
Histological Transformation

Introduction: Genome wide-association studies (GWAS) identified specific constitutional single nucleotide polymorphisms (SNPs) at risk for follicular lymphoma (FL). Top SNP is localized in HLA region (rs12195582). Five genome wide significant loci have been identified outside of HLA region, including 11q23.3 (near CXCR5), 11q24.3 (near ETS1), 3q28 (near LPP), 18q21.33 (near BCL2), and 8q24 (near PVT1) in addition with three suggestive loci at 17q25.3 (near CYBC1), 3q13.33 (CD86), 18q12.3 (SLC14A2) (Skibola, Am J Hum Genet. 2014). We investigated if these nine known FL loci could affect response to immunochemotherapy, histological transformation and outcome of a subgroup of patients treated uniformly in the prospective PRIMA phase III study. Methods: Among the 1.193 patients included in the PRIMA study, 390 patients had genotyping of the nine SNPs associated with FL risk (HLA, rs12195582; CXCR5, rs4938573; ETS1, rs4937362; LPP, rs6444305; BCL2, rs17749561; PVT1, rs13254990; CYBC1, rs3751913; CD86, rs2681416; SLC14A2, rs11082438). DNA was extracted from peripheral blood mononuclear leukocytes before any treatment. The genotyping was performed using custom TaqMan genotyping assays as part of the FL GWAS (Skibola, Am J Hum Genet. 2014). Correlations between response to induction treatment, biopsy-proven histological transformation (HT) and progression free survival (PFS) were performed for the each nine SNP individually. We also computed a combined polygenic risk score (PRS) and the number of allele at risk (nbRA) using the 9 SNPs for each individual. The PRS is a weighted average of the number of risk alleles with the weights being the log of the odds-ratio (OR) reported in the FL GWAS (Skibola, Am J Hum Genet. 2014). Survival analyses were stratified on FLIPI score and randomized arm (rituximab maintenance or observation). Piecewise cox models with pre-specified cutoffs at 2 years and 5 years were used to study early and late relapses. This work is supported by the French NCI (INCA, PRT-K16-167). Results: Among the 390 patients who received immunochemotherapy in the PRIMA study, 173 were randomized in rituximab maintenance arm, 166 were observed and 51 were not randomized. Complete response (CR) and unconfirmed CR were achieved in 251 patients (68%) at the end of induction phase. HT was documented in 16 patients (18%) among the 91 patients who had a biopsy with histological documentation at relapse. With a median follow-up of 9.8 years, the 5-year PFS since registration date for the whole cohort was 57% (95%CI, 52-62), 71% (95%CI, 64-78) in the rituximab maintenance arm, 47% (95%CI, 40-56) in the observation arm, and 39% (95%CI, 27-56) for the patients not randomized, thereby confirming the results of the PRIMA study. SNP rs17749561 C>T (CC, n=326; CT+TT, n=61) at 18q21.33 near BCL2 (HRCT/TT: 2.13; 95%CI, 1.20-3.70, P=0.009) and SNP rs3751913 A>G (AA, n=292; AG+GG, n=90) at 17q25.3 near CYBC1 (HRAG/GG: 1.83; 95%CI, 1.12-2.99, P=0.016) influenced the quality of response after induction therapy (CR/CRu versus partial response, stable and progressive disease) after FLIPI stratification but not PRS and nbRA. HT was not influenced by the allele status of the 9 individual SNPs, nor PRS and nbRA with the limitation of the low numbers of events. rs3751913 A>G near CYBC1 influenced PFS with 5-year PFS rates of 55%, 63% and 30% for patients with AA (n=293), AG (n=80) and GG (n=10) (P=0.036), respectively, with the limitation of the low number of patients with GG genotype. No association with PFS was observed for the remaining SNPs and when the 9 alleles were combined in a PRS or nbRA analyzed as continuous variables or per quantiles. We then investigated the susceptibility SNPs could influence early or late relapse. Using Piecewise cox models, we globally did not observe any influence on the risk of relapse in the 2 years after registration, between 2 and 5 years and after 5 years of SNPs analyzed individually by PRS or nbRA. Conclusions: Two susceptibility SNPs for FL identify by GWAS near BCL2 and CYBC1 genes influenced the quality of the response after induction therapy by immunochemotherapy. CYBC1 gene codes for cytochrome b-245 chaperone 1, a member of multi-subunit phagocyte NADPH oxidase. These results require replication in an independent cohort. Overall, susceptibility SNPs for FL are not associated with HT and PFS in this cohort of patients. Disclosures Cartron: Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Brice:Millennium Takeda: Research Funding; Takeda France: Consultancy, Honoraria; BMS: Honoraria. Salles:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria.

scholarly journals Baseline Suvmax Did Not Predict Histological Transformation from Follicular Lymphoma to Aggressive Lymphoma in the Phase III GALLIUM Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4160-4160 ◽  
Author(s):  
Farheen Mir ◽  
Sally F Barrington ◽  
Michel Meignan ◽  
Helen Brown ◽  
Tina Nielsen ◽  
...  
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
Research Funding ◽  
Performance Status ◽  
Bone Marrow Involvement ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
Phase Iii ◽  
Aggressive Lymphoma ◽  
Histological Transformation

Abstract Introduction: Follicular lymphoma (FL) generally has an indolent clinical course, but there is a 1-2% annual rate of histological transformation (HT) into aggressive lymphoma. Nodal HT sites have a higher maximum standardized uptake value (SUVmax) than non-transformed sites, and patients with HT typically show greater variation in SUVmax between sites. Upfront identification of patients at high risk of HT would allow physicians to consider treatment intensification. The objective of this analysis was to assess the relationship between baseline SUVmax (bSUVmax) and HT in the GALLIUM study (NCT01332968). Methods In the randomized, phase III GALLIUM study, 1202 previously untreated patients with grade 1-3a FL were randomized to receive induction with either obinutuzumab (GA101; G)- or rituximab (R)-based immunochemotherapy. Patients who responded received maintenance therapy with the same antibody. The primary endpoint of investigator-assessed progression-free survival was significantly improved in the G arm relative to the R arm (hazard ratio 0.66; p=0.001). As an exploratory endpoint, the degree of 18-fluorodeoxyglucose (FDG)-avidity expressed by SUVmax was assessed in patients with baseline FDG positron emission tomography (FDG-PET) scans by an independent review committee. Results: Among 522 patients with available bSUVmax data, 13 (2.5%) experienced biopsy-confirmed HT to diffuse large B-cell lymphoma or Grade 3b FL after a median follow-up of 59 months. Patients with HT were older (median age 61 vs 56 years), and were more likely to have a poor performance status (Eastern Cooperative Oncology Group [ECOG] performance status 2: 15.4% vs 2.6%), present with high-risk Follicular Lymphoma International Prognostic Index (FLIPI; 61.5% vs 40.3%), and have bone marrow involvement (76.9% vs 52.9%) than those without. More than 65% of patients showed bSUVmax >10, but only a minority of these experienced HT. Median (range) bSUVmax in patients with versus without HT was 12.4 (8.14, 27.95) versus 11.8 (3.05, 64.43), respectively. Median (range) baseline SUVrange (bSUVrange), defined as the difference between bSUVmax of the most and least FDG-avid lymphoma sites, was 6.6 (1.08, 23.91) versus 7.14 (0.00, 59.81), respectively (Figure). Conclusions: bSUVmax >10 is common in patients with previously untreated FL and is rarely associated with early HT. Neither bSUVmax nor bSUVrange predicted HT in GALLIUM, suggesting there may be little benefit in re-biopsy of lesions to exclude HT before commencing therapy. Better markers for identification of FL patients at risk of transformation are needed. Disclosures Mir: F. Hoffmann-La Roche: Employment. Barrington:F.Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees; Department of Health (England): Research Funding; MRC: Research Funding; CRUK: Research Funding; EPSRC: Research Funding; National Institute of Health Research: Research Funding. Meignan:F. Hoffman-La Roche Ltd: Honoraria. Brown:PAREXEL, external business partner with Roche Products Ltd, Welwyn, UK: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Sahin:F. Hoffman-La Roche Ltd: Other: Ownership interests PLC. Trotman:F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Janssen: Other: Unremunerated member of Ad Board, Research Funding; Beigene: Research Funding; Takeda: Other: Unremunerated member of Ad Board; Celgene: Other: Unremunerated member of Ad Board, Research Funding; PCYC: Research Funding.

Randomized, multicentre phase II trial of the sequencing of radium-223 and docetaxel plus prednisone in symptomatic bone-only metastatic castration-resistant prostate cancer (mCRPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS396-TPS396
Author(s):  
Vincenza Conteduca ◽  
Stefano Severi ◽  
Stefania Gori ◽  
Luca Galli ◽  
Michele Aieta ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Progression Free Survival ◽  
Sequential Therapy ◽  
Second Step ◽  
Type I ◽  
Castration Resistant Prostate Cancer ◽  
Multicentre Phase ◽  
Radium 223

TPS396 Background: Currently, the challenge is to reach a consensus on the best way to sequence different therapies for mCRPC patients (pts) in terms of efficacy and tolerability. Radium223 is a novel survival-prolonging targeted-α-therapy, but timing of its use in the treatment sequence of mCRPC remains an unanswered question, given the wide availability of therapeutic options Methods: This is a prospective, multicenter, randomized phase II study in symptomatic bone-only mCRPC pts who progressed after any androgen deprivation therapy, abiraterone and/or enzalutamide. Pts will be randomized 1:1 to receive radium223 initially followed by docetaxel+prednisone at the time of progression, or docetaxel+prednisone initially followed by radium223 at progression. In both treatment arms, the second step will be optional according to clinical evolution of disease (clinical deterioration and/or development of visceral metastases); however, each patient that will not enter in the second step will be still evaluable for the objectives of the study. No stratification factor will be used for randomization. Primary endpoint is to determine the better tolerated sequencing between radium223 and docetaxel in terms of health-related quality of life after completing the sequence and separately after each treatment. Based on primary endpoint, considering a type I error 0.1, type II error 0.2, proportion of responder pts in the standard arm 0.1 and in the experimental arm of 0.4, and assuming 10% loss to follow-up, a total of 70pts (35 for each arm) will be enrolled in the study. The study duration will be 36months; 15months of accrual, and 1 year of follow-up on the last participant enrolled. Secondary endpoints are to compare overall/progression-free/total progression free survival in pts treated with sequential therapy between radium223 and docetaxel. Additional secondary objective is to identify predictive factors for radium223 therapy, including potential circulating biomarkers through the plasma collection from all enrolled pts at different timepoints and the early prognostic role of functional imaging, such as PET with choline and/or PSMA. Clinical trial information: NCT03230734.

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