Interim Report of the UKCLL02 Trial: A Phase II Study of Subcutaneous Alemtuzumab Plus Fludarabine in Patients with Fludarabine Refractory CLL (on Behalf of the NCRI CLL Trials Sub-Group).

Abstract Patients with fludarabine refractory CLL have a median survival of 10 months with conventional chemotherapy. Intravenous (IV) alemtuzumab is approved in fludarabine refractory CLL resulting in 33 to 50% responses. Combined alemtuzumab and fludarabine can induce responses in CLL refractory to both agents. Infusion reactions and 2-hour infusions 3x a week for 12 weeks are problems with IV alemtuzumab. Subcutaneous (SC) alemtuzumab is more convenient but pharmacokinetics suggest the need for prolonged therapy with little efficacy data in fludarabine-refractory CLL. We report on the UKCLL02 study to assess the safety and effectiveness of SC alemtuzumab in fludarabine-refractory CLL. SC alemtuzumab was given at a dose of 30mg 3x a week (after dose escalation) for up to 24 weeks depending on 6-weekly marrow assessments. Patients failing to respond to alemtuzumab in the trial could receive oral fludarabine (40mg/m2/day for 3 days every 4 weeks) combined with SC alemtuzumab. In this planned interim analysis of the first 44 patients (median age 66, range 41 to 79) 2 patients died before receiving alemtuzumab, and 5 remain on therapy. Of the remaining 37 patients, one withdrew consent and 36 patients have completed therapy. Responses to alemtuzumab monotherapy (n=36) were 2 MRD negative CR, 1 MRD positive CR, 11 PR (including 1 MRD negative patient who remained cytopenic), 20 NR and 2 died. Alemtuzumab was given for a median 12 weeks (range: 2–24) with a median dose of 913mg (range 106 to 2173mg). 12 patients (8 NR and 4 PR) received concurrent fludarabine and SC alemtuzumab (median 2.5 courses fludarabine [range 1–3]). 2 non-responders achieved a PR and one of the partial reponders achieved a CR (MRD positive). Therefore the overall response rate for the whole cohort was 16/36 (44%) including 3 MRD negative patients (2 CRs and 1 PR). IgVH gene was unmutated (>98% homology to germ line DNA) in 11/14. FISH revealed poor risk deletions (11q and/or 17p) in 21/34 patients (17p- in 9; 11q- in 6 and both in 6). p53 functional analysis is available for 23. 20/23 had p53/ATM dysfunction or deletion. 10/21 evaluable cases with del (11q23)/del (17p) responded to therapy. The initial alemtuzumab dose was associated with localised erythematous skin reactions in 20 patients (diameter 1 to 18cm), fever in 7 and rigors in 3. All reactions subsided in <48h. Serious infections during alemtuzumab monotherapy were: CMV reactivation (10); febrile neutropenia (9); invasive fungal infection (3); pneumonia (2). On the combination, CMV reactivation in 2 cases but no other grade 3+ infections. All CMV reactivations resolved on antiviral therapy. Grade 3+ thrombocytopenia and neutropenia was seen in 16 and 25 patients on alemtuzumab monotherapy as well as in 1 and 2 patients on combined therapy, respectively. In summary, we report that subcutaneous alemtuzumab is effective in poor-risk fludarabine-refractory CLL and is well tolerated compared to IV therapy. A longer duration of SC alemtuzumab therapy (up to 24 weeks) is required. The addition of oral fludarabine improves the response rates with acceptable toxicity.

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Final Report of the UKCLL02 Trial: A Phase II Study of Subcutaneous Alemtuzumab Plus Fludarabine in Patients with Fludarabine Refractory CLL (on Behalf of the NCRI CLL Trials Sub-Group).

Blood ◽

10.1182/blood.v108.11.34.34 ◽

2006 ◽

Vol 108 (11) ◽

pp. 34-34 ◽

Cited By ~ 5

Author(s):

Hazem A. Sayala ◽

Paul Moreton ◽

Richard A. Jones ◽

Andy C. Rawstron ◽

Sheila J. O’Connor ◽

...

Keyword(s):

Median Survival ◽

Germ Line ◽

Combined Therapy ◽

Final Report ◽

Functional Assay ◽

Skin Reactions ◽

Poor Risk ◽

Erythematous Skin ◽

Grade 3 ◽

Cmv Reactivation

Abstract Patients with fludarabine refractory CLL have a median survival of 10 months with conventional chemotherapy. Intravenous (IV) alemtuzumab results in 33 to 50% responses in refractory CLL. Combined alemtuzumab and fludarabine can induce responses in CLL refractory to both agents. Infusion reactions and 2-hour infusions 3× a week for 12 weeks are problems with IV alemtuzumab. Subcutaneous (SC) alemtuzumab is more convenient but pharmacokinetics reveal lower initial levels compared to IV. The UKCLL02 study assessed the safety and efficacy of SC alemtuzumab in fludarabine-refractory CLL. SC alemtuzumab was given at a dose of 30mg 3× a week (after dose escalation) for up to 24 weeks depending on 6-weekly marrow assessments. Patients failing to respond to alemtuzumab could receive oral fludarabine (40mg/m2/day for 3 days every 4 weeks) combined with SC alemtuzumab. Of 53 patients (median age 64, range 41 to 79) enrolled 2 patients died before receiving alemtuzumab and 1 withdrew consent. 50 patients have completed therapy and 49 are evaluable. Responses to alemtuzumab monotherapy (n=49) were 5 MRD negative CR, 2 MRD positive CR, 15 PR (including 1 MRD negative patient who remained cytopenic), 25 NR and 2 patients died on treatment. Alemtuzumab was given for a median of 18.8 weeks (range:1.6–24) with a median dose of 1370.5mg (range 106–2323mg). 17 patients (6 PRs and 11 NRs) received concurrent fludarabine and SC alemtuzumab (median 2 courses fludarabine [range 1–3]). 2 NR achieved a PR and 1 PR achieved a CR (MRD positive). Therefore the overall response rate for the whole cohort was 24/49(49%) including 6 MRD negative patients (5CRs and 1 PR). IgVH gene was unmutated (>98% germ line homology ) in 23/31 patients. FISH revealed poor risk deletions (11q and/or 17p) in 28/46 patients (17p- in 15, 11q- in 7, both in 6). 25/38 patients had dysfunction p53 in a functional assay. 22/38 patients (58%) with poor risk deletions (11q- and/or 17p-) and/or p53 dysfunction responded to treatment, including 5 patients who achieved MRD-negative CRs, 3 MRD-positive CR, and 14 PR. The initial alemtuzumab dose was associated with localised erythematous skin reactions in 26 patients (diameter 1 to 18cm), fever in 8 and rigors in 4. All reactions subsided in <48h. Serious infections during alemtuzumab monotherapy were: CMV reactivation (18); febrile neutropenia (10); invasive fungal infection (4); pneumonia (7) and septicaemia (2). On the combination, CMV reactivation (3 cases) and septicaemia in (1). All CMV reactivations resolved on antiviral therapy. Grade 3+ thrombocytopenia and neutropenia was seen in 26 and 41 patients on alemtuzumab monotherapy as well as in 1 and 5 patients on combined therapy, respectively. The median survival for responders was 25 months compared to 13 months for non-responders. In summary, we report that subcutaneous alemtuzumab is effective in poor-risk fludarabine-refractory CLL and is well tolerated compared to IV therapy. A longer duration of SC alemtuzumab therapy (up to 24 weeks) was given. The addition of oral fludarabine improves the response rates with acceptable toxicity.

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Updated Results of Combination Cytokine Immunotherapy In the Treatment of Aplastic Anemia and Myelodysplastic Syndrome (MDS)

Blood ◽

10.1182/blood.v116.21.2920.2920 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2920-2920 ◽

Cited By ~ 4

Author(s):

Tapan Kadia ◽

Farhad Ravandi ◽

Guillermo Garcia-Manero ◽

Elias Jabbour ◽

Gautam Borthakur ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Supportive Care ◽

Aplastic Anemia ◽

Oral Prednisone ◽

Disease Free Survival ◽

International Prognostic Scoring System ◽

Serious Infections ◽

Common Grade ◽

Infusion Reactions ◽

Grade 3

Abstract Abstract 2920 Immunosuppressive therapy using antithymocyte globulin (ATG) and cyclosporine has been successfully used in the treatment of cytopenias in patients (pts) with severe aplastic anemia (AA). Laboratory and clinical data suggest that dysregulated immune mechanisms may also contribute to the pathogenesis of ineffective hematopoiesis in some subsets of early MDS and result in cytopenias. Rabbit ATG (rATG) is active and well tolerated in pts have recurrent/persistent disease after treatment with equine ATG. Here we present our updated results with a combination of rATG, cyclosporine, prednisone, and G-CSF in pts with aplastic anemia or myelodysplastic syndrome. This is a single-arm phase II study evaluating the efficacy and safety of the following combination in pts with aplastic anemia and low or intermediate-1 risk MDS (by the international prognostic scoring system) : rATG 3.5 mg/kg/day (or 2.5 mg/kg/day for age ≥ 55 yrs) intravenously (IV) for 5 days, methylprednisone 1mg/kg/day IV daily for 5 days (given prior to each dose of ATG), followed by oral prednisone tapered off over 1 month, G-CSF (filgrastim daily or pegfilgrastim every 2 weeks) subcutaneously for up to 3 months, and cyclosporine (5 mg/kg) daily for up to 6 months. Dose reductions or interruptions for toxicities were allowed at the discretion of the treating physician. Responses were assessed at 3 months after initiating therapy. Of the 51 pts enrolled, 46 have received treatment including 23 (50%) pts with AA and 23 (50%) pts with MDS. The median age overall was 60 yrs (range, 19–82), 54 (19-82) in the AA and 63 (48-79) in the MDS cohorts respectively. Of the 43 pts evaluable for response (21 AA, 22 MDS), there were 13 (62%) responders (4 CR, 8 PR, 1 HI) in AA cohort and 6 (27%) responders (2 CR, 4 HI) in the MDS cohort. Median age of responders was 59 (19-79). The median time to response (TTR) was 3.2 months. Of the 46 pts who received treatment, 20 pts (43%) were HLA-DR15 positive, 22 (48%) were negative, and 4 (9%) were not checked. In the MDS cohort, 9 (39%) pts were HLA-DR15 positive and none responded. In the AA cohort, 11 (48%) were HLA-DR15 positive, out of which 6 (55%) responded. Among the 19 responding pts described above, 6 (32%) were HLA-DR15 positive and all had AA. The median disease free survival for responders (CR & PR) is 26 months. The median overall survival of responders has not been reached, compared to 20 months for nonresponders (p<0.001). Overall the treatment was tolerable. The most common grade 3/4 toxicities were thrombocytopenia (43%), neutropenia (41%), transaminase elevation (13%), hyperbilirubinemia (7%), infection/fever (7%), and hyperglycemia (4%). Grade 3/4 dyspnea, abdominal pain, and hypertension occurred in 1 patient each. Twenty pts (43%) had infusion related reactions including fever, chills, and dyspnea that was manageable with supportive care. The combination of rATG, cyclosporine, steroids, and G-CSF is a well tolerated, effective regimen in the treatment of aplastic anemia and also has activity in a subset of pts with MDS. The rate of serious infections was relatively low, but infusion reactions were common and should be managed with premedication and supportive care. HLA-DR15 positivity correlated with response in patients with AA, but not in MDS. Responses were slow to occur, but durable, and associated with improved survival. Disclosures: Kadia: Genzyme: Research Funding. Ravandi:Genzyme: Honoraria.

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Combination of trastuzumab, pertuzumab and docetaxel in patients with advanced non-small cell lung cancer (NSCLC) harboring HER2 mutation: Final results from the IFCT-1703 R2D2 trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9015 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9015-9015

Author(s):

Julien Mazieres ◽

Claire Lafitte ◽

Charles Ricordel ◽

Laurent Greillier ◽

Jean-Louis Pujol ◽

...

Keyword(s):

Brain Metastases ◽

Overall Response Rate ◽

Advanced Nsclc ◽

Response Rate ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Loading Dose ◽

Overall Response ◽

Grade 3 ◽

Exon 20

9015 Background: Human epidermal growth factor receptor 2 ( HER2) exon 20 insertions and mutations are oncogenic drivers found in 1-2% of NSCLC. However, there are no approved therapies for these patients. Many studies suggest that the use of HER2 inhibitors developed for breast cancer patients might be of interest in this setting. The aim of this trial was to prospectively evaluate the interest of a combination of two antibodies against HER2 (trastuzumab and pertuzumab) with docetaxel. Methods: IFCT-1703 R2D2 trial is a multicenter, non-randomized phase 2 study with a two-stage design, a power of 90% and an alpha risk at 5% (one-sided). HER2 mutational status was assessed locally in certified molecular genetic centers. Main other inclusion criteria were advanced NSCLC, progression after ≥ 1 platinum-based chemotherapy, asymptomatic brain metastases, left ventricular ejection fraction (LVEF) ≥ 50%, and PS 0-2. Patients were treated every 3 weeks with pertuzumab at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at a loading dose of 8 mg/kg and 6 mg/kg thereafter; and docetaxel at 75 mg/m². Treatment was given until toxicity or disease progression. The primary outcome was overall response rate (ORR). Other endpoints included duration of response, progression-free survival and safety. NCT number: NCT03845270. Results: From May 2019 to October 2020, 45 patients were enrolled in 17 centers and received study treatment. Median age was 64.5 years (range 31–84), 72% females, 35% smokers, 100% non-squamous histology and 15% with ECOG PS 2. 31.1% patients had brain metastases. PD-L1 was expressed ≥ 1% and ≥ 50% in 36% and 7% of the patients, respectively. No other oncogene driver was found associated with HER2 exon 20 mutation. With a median follow-up of 12 months, 44 (98%) patients were evaluable for the primary endpoint. Overall response rate was 29% (n = 13), stable disease 56% (n = 26). Median PFS was 6.8 months (95% CI[4.0-8.5]). Median duration of treatment in patients with confirmed response (n = 13) was 10 months (95% CI[2.7-14.9]). At the time of data cut-off, 15 patients (33%) were still under treatment. Grade 3/4 treatment-related adverse events (AEs) were observed in 64% of patients. No patient experienced treatment discontinuation because of toxicity. One sudden death was possibly related to treatment. Most frequent grade ≥ 3 AEs were neutropenia (33%), diarrhea (13%) and anaemia (9%). Grade 1/2 dyspnea was observed in 3 (6.7%) patients. No ILD were reported. Variation LVEF was -1.72% on average (min: -18 %; max: 10 %). Conclusions: The triplet trastuzumab, pertuzumab and docetaxel is feasible and active in HER2 pretreated advanced NSCLC. These results confirm the activity of HER2 antibodies-based strategy which should be considered in these patients. Clinical trial information: NCT03845270.

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Time to Progression Post-Induction Predicts Outcomes of Ixazomib Based Therapy for Relapsed/Refractory Myeloma: Real World Data from a Multi-Site Israeli Registry Study

Blood ◽

10.1182/blood-2018-99-114217 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1972-1972

Author(s):

Yael C Cohen ◽

Hila Magen ◽

Noa Lavi ◽

Moshe E. Gatt ◽

Evgeni Chubar ◽

...

Keyword(s):

Research Funding ◽

Overall Response Rate ◽

Target Organ Damage ◽

Progression Free Survival ◽

Organ Damage ◽

Real World Data ◽

Free Survival ◽

Grade 3 ◽

Indolent Disease

Abstract Introduction Ixazomib is an orally available proteasome inhibitor, shown to be safe and efficacious in combination with lenalidomide and dexamethasone (IRd regimen) in patients with relapsed and refractory multiple myeloma (RRMM) with 1-3 prior lines, demonstrating a progression free survival (PFS) benefit which was similar across cytogenetic risk groups (Tourmaline-MM1 phase 3 trial). A European real world data analysis of an IRd named patient program (NPP) outcomes in Greece (n=35), UK (n=46) and Check republic (n=57) showed similar favorable outcomes (Terpos et al, Blood 2017 130:3087). We aimed to analyze outcomes of ixazomib combinations among a multi-site cohort in the Israeli Myeloma registry. Overall response rate (ORR) was classified according to IMWG criteria. Primary endpoint was PFS, secondary endpoints included ORR, overall survival (OS), safety and tolerability. Patients A total of 78 patients across 7 sites, who received at least one cycle of ixazomib combination between June 2013 and June 2018 for treatment of RRMM were retrospectively included. Median age was 68 (range: 38-90). Male/Female ratio was 42/36. ISS (rISS) I/II/II was 30%/42%/27% (25%/54%/15%). Patient received between 1 and 7 prior lines of therapy, 66% received ixazomib in 2nd line, 18% in 3rd line. Overall, 89% of patients had been exposed to PIs (bortezomib 86%) prior to IRd, 41% to IMiDs (thalidomide 28% lenalidomide 22% and pomalidomide 6%), and 35% had undergone autologous transplantation (ASCT). Induction treatment was mostly bortezomib based (85%), most frequently VCD (62%). FISH cytogenetics were available for 60 patients, 29 (48%) had high or intermediate risk aberrations (t(4:14) 12 pts, amp 1q21 12 pts, del17p 9 pts). Disease aggressiveness was classified by treating physician as indolent (rapid control to protect from target organ damage not required) vs aggressive (imminent target organ damage) in 63% vs 27%, respectively. 60 (77%) of the 78 patients received ixazomib via a named patient program, the rest via national or private healthcare provider. Results Median time of follow up from first ixazomib dose was 22 months (range: 1-39 months), and 54 months from diagnosis of myeloma. Treatment is ongoing in 44 (56%) patients with a median duration of 19 months (range: 1-29). Among patients who discontinued treatment, the median duration was 9 months (1-31). Ixazomib was combined with lenalidomide, pomalidomide, and daratumumab in 69%, 9% and 4%, respectively. Overall response rate was 88% - CR 10%, VGPR 36%, PR 42%. Progression free survival was 78% and 54% at 12 and 24 months, respectively (fig1a). A worse PFS was found with physician assessment of aggressive vs indolent disease (14.5 vs 25.9 months, p=0.001), and with post induction progression free period (PFS1) ≤ 24 months vs. >24 months (23.9 vs 31.5 months, p=0.038) (fig 1b); age >=65 trended towards a worse PFS (p=0.058). Poor cytogenetic risk, prior exposure to bortezomib, prior auto transplant, and number of prior lines of therapy did not affect PFS or ORR. OS from first ixazomib administration was 90% and 81% at 12 and 24 months, respectively; median OS was not reached (fig1a). Any (grade 3-4) toxicity considered by investigator as related to ixazomib was reported in 70% (18% grade 3-4), including neutropenia 14% (6%), anemia 19% (6%), thrombocytopenia 17% (5%), nausea and vomiting 17% (1%), DVT/PE 4% (1%), neutropenic infection 0 (4%), peripheral neuropathy 14% (3%), diarrhea 14% (3%), rash 10% (4%), pneumonia 5% (3%). There were no ixazomib related deaths. Dose reduction or discontinuation due to toxicity occurred in 28% and 12%, respectively. Conclusion Our data shows ixazomib-based combinations are efficacious and safe regimens for patients with RRMM, achieving ORR of 88%, at 2nd as well as later lines of therapy, regardless to cytogenetic risk. Over a median follow up of almost 2-years, 54% remained progression free at 24 months. An ixazomib based regimen may be particularly attractive for patients who remain progression free for more than 24 months after a bortezomib induction and for patients with a more indolent disease phenotype. Disclosures Cohen: Neopharm Israel: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Medisson Israel: Consultancy, Honoraria, Research Funding. Tadmor:NOVARTIS: Consultancy; PFIEZER: Consultancy; ABBVIE: Consultancy; JNJ: Consultancy; ROCHE: Research Funding.

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SAT0149 EXPOSURE-RESPONSE RELATIONSHIPS FOR EFFICACY AND SAFETY OF FILGOTINIB AND ITS METABOLITE GS-829845 IN SUBJECTS WITH RHEUMATOID ARTHRITIS BASED ON PHASE 2 AND PHASE 3 STUDIES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4977 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1013-1014

Author(s):

A. Meng ◽

K. Anderson ◽

C. Nelson ◽

B. Kirby ◽

L. Ni ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Response Rates ◽

High Response ◽

Phase 2 ◽

Phase 3 ◽

Once Daily ◽

Exposure Response ◽

Serious Infections ◽

Wide Range ◽

Grade 3

Background:Filgotinib is an orally administered small molecule that provides selective inhibition of JAK1, a signaling molecule that helps drive inflammatory pathways underlying rheumatoid arthritis (RA).Objectives:Exposure-response (ER) analyses were performed for efficacy following completion of Phase 2 studies over a wide range of doses to support evaluation of 200mg and 100 mg once daily in Phase 3 studies. ER analyses were subsequently performed by using Phase 3 efficacy data to support selection of the proposed registrational dose. ER analyses for safety based on pooled Phase 2 and Phase 3 studies were conducted to examine the safety of evaluated doses.Methods:Population PK analyses were conducted to estimate plasma exposures of filgotinib and GS-829845 (major circulating active metabolite of filgotinib) in both Phase 2 (DARWIN 1 and DARWIN 2) and Phase 3 studies (FINCH 1, FINCH 2, and FINCH 3) encompassing a dose range of 25 to 100 mg twice daily and 50 to 200 mg once daily. As both filgotinib and GS-829845 contribute to efficacy via JAK1 inhibition, their exposures were combined into single parameters, AUCeff and Ctau-eff (effective area under the curve and effective concentration at trough, by accounting for relative inhibition potency and molecular weight) in the ER analyses for various efficacy endpoints (e.g ACR20/50/70 responses) at Week 12 and Week 24. The ER analyses for safety endpoints (the 5 most frequent treatment-emergent adverse events [TEAEs] and Grade 3 or 4 laboratory abnormalities, serious TEAEs, and serious infections) were performed separately for filgotinib and GS-829845 exposures to characterize the individual safety profile of each analyte. The 5 evaluated TEAEs were nausea, nasopharyngitis, upper respiratory tract infection, headache, and hypertension; the 5 Grade 3/4 laboratory abnormalities included lymphocytes decrease, glucose increase, phosphate decrease, triacylglycerol lipase increase, and creatine kinase increase.Results:In the ER analyses for efficacy based on Phase 2 studies, high response rates were demonstrated in ACR20/50/70 across all octile groups in subjects with RA receiving filgotinib and the ER supported further evaluation of both 200 mg and 100 mg once daily doses in Phase 3 clinical studies. Similarly, ER relationships based on pooled Phase 3 studies across various endpoints (e.g ACR20/50/70) consistently revealed high response rates across the exposure range for both the filgotinib 200 mg and 100 mg doses. A trend of increasing response with increasing exposure was observed over the exposure range for multiple secondary efficacy endpoints including ACR50 and ACR70 with the effective exposures at filgotinib 200 mg primarily residing on the plateau of the ER curves.Filgotinib was generally well-tolerated with no individual TEAE or Grade 3 or 4 laboratory abnormality > 5% in the filgotinib 200 mg once daily group up to Week 12. No relationships were observed between filgotinib and GS-829845 exposures (AUC0-24 and Cmax) and the most frequent TEAEs, Grade 3/4 laboratory abnormalities, serious TEAEs, or serious infections up to Week 52.Conclusion:ER analyses demonstrate that both the 200 mg and 100 mg once daily filgotinib doses are efficacious in subjects with moderately to severely active RA without clear dose-dependent effects on safety. The trend towards greater efficacy with higher exposures for some secondary endpoints (ACR50 and ACR70) and a lack of exposure-safety relationship supports a dose of 200 mg once daily over 100 mg once daily since it presents the best benefit/risk ratio among the doses tested.Disclosure of Interests: :Amy Meng Shareholder of: Gilead Sciences, Employee of: Gilead, Kacey Anderson Shareholder of: Gilead Sciences, Employee of: Sciences, Cara Nelson Shareholder of: Gilead, Employee of: Gilead, Brian Kirby Shareholder of: Gilead, Employee of: Gilead, Liyun Ni Shareholder of: Gilead, Employee of: Gilead, Shu-Min Chuang Shareholder of: Gilead, Employee of: Gilead, Brian Kearney Shareholder of: Gilead, Employee of: Gilead, Anita Mathias Shareholder of: Gilead, Employee of: Gilead

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Biweekly Raltitrexed in Combination with Irinotecan (RIR) as Second-Line Therapy for Patients with Metastatic Colorectal Cancer: A Non-Randomized, Open-Label Phase II Trial.

10.21203/rs.3.rs-80934/v1 ◽

2020 ◽

Author(s):

Ke Cheng ◽

Yu-Wen Zhou ◽

Ye Chen ◽

Zhi-Ping Li ◽

Meng Qiu ◽

...

Keyword(s):

Adverse Events ◽

Overall Response Rate ◽

Progression Free Survival ◽

Second Line ◽

Open Label ◽

Second Line Therapy ◽

Free Survival ◽

Common Grade ◽

Open Label Phase ◽

Grade 3

Abstract Background Irinotecan-based doublet chemotherapy strategy was standard second-line backbone treatment for patients with oxaliplatin‑refractory metastatic colorectal cancer(mCRC). The aim of this study was to evaluate tolerability and efficacy of raltitrexed combined with irinotecan biweekly administered as the second-line therapy for mCRC patients.Methods The study was a single-center, non-randomized, open-label phase II trial. Patients with mCRC after failure with first-line treatment of oxaliplatin and fluoropyrimidine or its derivatives were enrolled. Irinotecan (180 mg/m2) and raltitrexed (2.5 mg/m2) were given intravenously on day 1. Cycles were repeated every 2 weeks. The primary endpoint was progression-free survival, and the secondary endpoints included overall response rate, disease control rate, overall survival and treatment related adverse events. Results Between December 2012 and October 2016, 35 patients were enrolled. 33 and 35 patients were assessed for response and safety, respectively. The overall response rate (ORR) was 8.6 %, and the disease control rate (DCR) was 71.4%. The median progression-free survival (PFS) was 4.5 months (95% CI 3.8–5.2). The median overall survival was 12.0 months (95% CI 8.5–15.5). Four patients received conversion therapy to no evidence of disease (NED), and 2 patients were still alive with beyond 24 months survival. The most common grade 3/4 hematological adverse events were leukopenia (8.6%), neutropenia (5.7%). The most common grade 3/4 nonhematological adverse events were anorexia (14.3%), vomiting (14.3%), nausea (11.4%) and fatigue (8.6%). Two patients discontinued the protocol treatment because of treatment-related gastrointestinal adverse events. No one died from treatment-related events. The incidence and severity of toxicity was irrelevant to UGT1A1 status.Conclusions The combination of irinotecan with raltitrexed is an active, convenient and acceptable toxic regimen for second-line treatment for mCRC patients, which needs further study as a chemotherapy backbone to be combined with targeted agents in mCRC.Trial registration No. ChiCTR-ONC-12002767. The study was registered with the Chinese Clinical Trial Registry at 29 Octorber 2012, http://www.chictr.org.cn/index.aspx.

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Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.20.02259 ◽

2020 ◽

pp. JCO.20.02259

Author(s):

Paul G. Richardson ◽

Albert Oriol ◽

Alessandra Larocca ◽

Joan Bladé ◽

Michele Cavo ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Overall Response Rate ◽

Response Rate ◽

Progression Free Survival ◽

Free Survival ◽

Duration Of Response ◽

Heavily Pretreated ◽

Grade 3

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

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Capecitabine As First-Line Treatment for Patients Older Than 70 Years With Metastatic Colorectal Cancer: An Oncopaz Cooperative Group Study

Journal of Clinical Oncology ◽

10.1200/jco.2005.06.035 ◽

2005 ◽

Vol 23 (13) ◽

pp. 3104-3111 ◽

Cited By ~ 94

Author(s):

Jaime Feliu ◽

Pilar Escudero ◽

Ferrán Llosa ◽

Matilde Bolaños ◽

Jose-Manuel Vicent ◽

...

Keyword(s):

Colorectal Cancer ◽

Elderly Patients ◽

Combination Chemotherapy ◽

Clinical Benefit ◽

Overall Response Rate ◽

Advanced Colorectal Cancer ◽

First Line ◽

Hand Foot Syndrome ◽

Clinical Benefit Response ◽

Grade 3

Purpose To determine the tolerability of capecitabine in elderly patients with advanced colorectal cancer (CRC). Patients and Methods Fifty-one patients with advanced CRC who were ≥ 70 years and considered ineligible for combination chemotherapy received oral capecitabine 1,250 mg/m2 twice daily on days 1 to 14 every 3 weeks. Patients with a creatinine clearance of 30 to 50 mL/min received a dose of 950 mg/m2 twice daily. Results A total of 248 cycles of capecitabine were administered (median, five cycles; range, one to eight cycles). The overall response rate was 24% (95% CI, 15% to 41%), including two complete responses (CR; 4%) and 10 partial responses (PR; 20%). Disease control (CR + PR + stable disease) was achieved in 67% of patients. The median times to disease progression and overall survival were 7 months (95% CI, 6.4 to 9.5 months) and 11 months (95% CI, 8.6 to 13.3 months), respectively. Of the 35 patients evaluated for clinical benefit response, 14 (40%; 95% CI, 24% to 58%) showed clinical benefit. Capecitabine was well tolerated. Treatment-related grade 3 and 4 adverse events were observed in only six patients (12%), and the most common events were diarrhea, hand-foot syndrome, and thrombocytopenia. One patient (2%) had an episode of angina, but no treatment-related deaths were reported. Conclusion Our findings suggest that capecitabine is effective and well tolerated in elderly patients with advanced CRC who are considered ineligible for combination chemotherapy.

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Second-Line Irinotecan, Leucovorin, and 5-Fluorouracil for Gastric Cancer Patients after Failed Docetaxel and S-1

Gastroenterology Research and Practice ◽

10.1155/2016/6857625 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Joo Young Jung ◽

Min-Hee Ryu ◽

Baek-Yeol Ryoo ◽

Boram Han ◽

Ji Woong Cho ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Response Rate ◽

Response Rate ◽

Antitumour Activity ◽

Metastatic Gastric Cancer ◽

Second Line ◽

First Line ◽

Previously Treated ◽

Grade 3 ◽

Gastric Cancer Patients

Background.This retrospective study aimed to assess the efficacy and toxicities of second-line chemotherapy with irinotecan, leucovorin, and 5-fluorouracil (5-FU) in metastatic gastric cancer (MGC) patients previously treated with docetaxel and S-1 with or without oxaliplatin (DS/DOS).Patients and Methods.We reviewed the data of patients who had previously been treated with first-line DS/DOS and received biweekly irinotecan-based chemotherapy (FOLFIRI/IFL) between October 2004 and November 2011.Results.A total of 209 cycles were administered to 35 patients, with a median of 4 (range, 1–22) cycles each. The overall response rate in 29 response-assessable patients was 17.2%, including 2 complete and 3 partial responses. The median progression-free and overall survivals were 3.81 (95% confidence interval [CI], 1.82–5.80) months and 6.24 (95% CI, 1.44–11.04) months, respectively. The major grade 3/4 toxicity was neutropenia (8.6%).Conclusion.FOLFIRI/IFL chemotherapy showed modest antitumour activity and tolerable toxicities in DS/DOS-treated MGC patients.

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Rituximab and abatacept

10.1093/med/9780199642489.003.0083 ◽

2013 ◽

Author(s):

John D. Isaacs ◽

Philip M. Brown

Keyword(s):

Cell Function ◽

Signs And Symptoms ◽

Clinical Excellence ◽

Soluble Form ◽

Target Cells ◽

It Use ◽

The United Kingdom ◽

Serious Infections ◽

Infusion Reactions ◽

Necrosis Factor

Two biologics that target cells have been licensed to treat rheumatoid arthritis (RA). Rituximab is a chimeric monoclonal antibody (mAb) against CD20 that depletes B cells; abatacept is a soluble form of CTLA-4 that blocks costimulation and interferes with T-cell function. Both drugs alleviate signs and symptoms of RA and have been shown to retard radiographic progression. Rituximab is licensed for use following failure of tumour necrosis factor (TNF) blockade whereas abatacept's licence permits it use as a first-line biologic. In the United Kingdom, however, the National Institute for Health and Clinical Excellence (NICE) restricts the use of abatacept to patients who develop adverse effects with rituximab or in whom rituximab is contraindicated. As with other biologics, the use of either drug is associated with an enhanced risk of serious infections; additionally, rituximab in particular can cause infusion reactions, requiring prophylaxis. By targeting cells that are central to RA pathogenesis, these drugs provide important additional therapeutic options for patients with RA.

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