Pomalidomide Plus Dexamethasone (Pd) in the Treatment of Asian Patients with Relapsed/Refractory Myeloma (RRMM) Who Are Previously Treated with Bortezomib and Refractory to Lenalidomide - Interim Analysis of a Trial By the Asian Myeloma Network (AMN)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2130-2130
Author(s):  
Wee J Chng ◽  
Kihyun Kim ◽  
Jeffrey Huang ◽  
Chor Sang Chim ◽  
Hiroshi Kosugi ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Median Duration ◽  
Prospective Trial ◽  
Safety Data ◽  
Published Data ◽  
Base Line ◽  
Asian Patients ◽  
Duration Of Response ◽  
Previously Treated ◽  
Grade 3

Abstract Background Pomalidomide is a 3rdgeneration immunomodulatory drug that has been approved for the treatment of Patients who progress after prior treatment with bortezomib and lenalidomide. Experience with pomalidomide in Asian patients is very limited till date. In addition, it is unclear if pomalidomide will work in patients who have been exposed to a newer generation of treatments for myeloma including carfilzomib, ixazomib, panobinostat and daratumumab. Method We conducted a prospective trial of pomalidomide (4mg daily for 21 days every 4 weeks) plus dexamethasone (40mg once weekly) in myeloma patients who have relapsed after prior bortezomib and are refractory to lenalidomide from Singapore, Korea, Japan, Hong Kong and Taiwan (NCT02158702). Patients were allowed up to 6 prior lines of treatment. If there is less than a minimal response after 3 cycles of pomalidomide and dexamethasone, including progression within 3 cycles, cyclophosphamide 300mg/m2can be added. The trial was started in December 2014 and is still ongoing. To date, 121 patients have been recruited. This interim report presents data available up till the data cut-off date of 30 April 2016. Results Eighty-six patients have available base line information and safety data. 55% of patients are male and median age of the cohort is 65 years old. 37% and 27% of patients are International Stage System (ISS) stage 2 and 3 respectively. 35% of patients have abnormal creatinine clearance. Median prior line of treatment is 4. 24% of patients required dose reduction of pomalidomide, 8% require dose reduction of dexamethasone. 70% of patients experience adverse events (AEs) of any grade (31% of episodes grade 3 or higher), with 35% of these episodes related to the study drugs. 47% of patients experienced serious AEs (SAEs) of any grade (91% of episodes grade 3 or higher), with 42% of these episodes related to the study drugs. Almost all of these events are related to cytopenias and infections. Only 1 patient experienced each of these AEs: grade 3 peripheral neuropathy, VTE or grade 3 renal impairment. Five patients withdrew due to toxicity. Fifteen patients died while on the study, 5 from disease progression, 2 from late stage disease, and 8 from sepsis or pneumonia. The median overall length of follow-up is 5 months. The overall median PFS (N=65) was 6.5 months. Those treated with only Pd (n=53) have a median PFS of 6.5 months. Patients with cyclophosphamide added (Pcd) had a median PFS of 5.8 months. Achievement of a partial response (PR) or better was significantly associated with improved PFS. There was no observed difference in PFS by age, number of prior lines of treatment, ISS stage or the presence of high-risk genetics. Overall median OS was 14 months. For those treated with only Pd, the median OS was 14 months whereas it is 10 months for those on Pcd. Forty-four patients have data for response assessment. 22 (50%) achieved a PR or deeper response with 1 achieving CR and 1 stringent CR. The median duration of response was 8.4 months for those who had achieved a PR or more. Eight out of those 44 patients required the addition of cyclophosphamide due to suboptimal response, 2 of whom subsequently achieved a PR. In these patients the median duration of response was 4.7 months. Eleven patients were previously treated with carfilzomib, ixazomib, panobinostat, elotuzumab or daratumumab in clinical trials. Amongst these, 6 (55%) obtained a PR or better and were able to maintain the response for 10 months. In this group, the PFS was 5.5 months and the median OS was 10.3 months. Conclusion This is the first prospective report of the efficacy and safety of Pd in Asian patients with RRMM. The combination is highly active in patients who are heavily pre-treated. Our results compare favorably with previously published data from the US and Europe. The regimen appears to be active across age groups, risk categories and prior lines of treatment. In particular, it is very active even in patients who have progressed following treatment with the latest generations of approved drugs including monoclonal antibodies. In patients who have a suboptimal response, the addition of cyclophosphamide can salvage meaningful response. The regimen is well tolerated and toxicity manageable. A randomized study comparing Pcd to Pd will commence soon. Disclosures Chng: Celgene: Honoraria, Research Funding. Sakamoto:Takeda Pharmaceutical: Consultancy; Yakult: Other: Remuneration. Durie:Amgen: Consultancy; Takeda: Consultancy; Janssen: Consultancy.

scholarly journals Phase 2 Study of Daratumumab in Combination with Thalidomide and Dexamethasone in Asian Patients with Relapsed/Refractory Myeloma (RRMM) - Interim Analysis of a Trial By the Asian Myeloma Network (AMN)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-21
Author(s):  
Wee-Joo Chng ◽  
Cindy Lin ◽  
Xinhua Li ◽  
Chandramouli Nagarajan ◽  
Sung-Soo Yoon ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Research Funding ◽  
Single Agent ◽  
Prospective Trial ◽  
Safety Data ◽  
Novel Agents ◽  
High Dose ◽  
Base Line ◽  
Asian Patients ◽  
Grade 3

Background Daratumumab is an anti-CD38 antibody with single agent activity in relapsed refractory myeloma. It has synergistic efficacy when combined with proteasome inhibitors (bortezomib and carfilzomib) or lenalidomide. However to date, the usefulness of the addition of thalidomide to Daratumumab has not been reported. This is particularly relevant as in much of Asia, combinations of 2 novel agents are not reimbursed and hence not accessible to most patients. Method We conducted a prospective trial of daratumumab (16mg/kg once a week for 8 weeks followed by once every 2 weeks for 16 weeks and then once every 4 weeks thereafter) plus thalidomide 100mg daily plus dexamethasone (40mg once weekly) in myeloma patients who have relapsed and/or refractory myeloma with up to 6 prior lines of treatment from Singapore, and Korea (NCT03143036). The trial was started in April 2018 and is ongoing. To date,42 of 70 patients have been recruited. This interim report presents data available up till the data cut-off date of 23 June 2020. Results Thirty-six patients have available base line information and safety data. 72% of patients are male and median age of the cohort is 67 years old. 39% and 25% of patients are International Stage System (ISS) stage 2 and 3 respectively. 50% of patients have abnormal creatinine clearance. Median prior line of treatment is 2. 94% of patients have prior Bortezomib, 33% had prior Carfilzomib and 17% had prior ixazomib. 58% had prior thalidomide and 44% had prior lenalidomide. 61% of patients had prior high dose melphalan and stem cell transplantation. 36% of patients required dose reduction of thalidomide or dexamethasone. 100% of patients experience adverse events (AEs) of any grade (25% of episodes grade 3 or higher), with 45% of these episodes related to the study drugs. 69% of patients experienced serious AEs (SAEs) of any grade (49% of episodes grade 3 or higher), with 34% of these episodes related to the study drugs. Almost all of these events are related to cytopenia and infections. Only 1 patient experienced grade 3 peripheral neuropathy, and 2 patients experiencegrade 3 renal impairment. Interestingly, only 2 patients develop an infusion reaction but both were able to complete the infusion with a temporary interruption, addition of montelukast and anti-histamines and resuming the infusion at a slower rate. At a median follow-up of 10.4 months for surviving patients, 7 of the 36 patients have died, and 11 have progressed. Five patients withdrew due to toxicity. Of the 36 patients included in this interim analysis, 3 achieved sCR, 3 CR, 10 VGPR, 10 PR giving an overall response rate of 72%. Conclusion This is the first study of Daratumumab combined with thalidomide and dexamethasone in Asian patients with RRMM. The combination appears to be highly active and well tolerated with manageable toxicity. This low cost daratumumab combination would be a good option for relapsed myeloma patients especially in countries where the treatment cost and reimbursement for combination containing 2 novel agents is not feasible or unavailable. Disclosures Chng: Amgen: Honoraria, Research Funding; Abbvie: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Yoon:Kyowahako Kirin: Research Funding; F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; Janssen: Consultancy; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; YuhanPharma: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Paclitaxel Is Safe and Effective in the Treatment of Advanced AIDS-Related Kaposi's Sarcoma

1999 ◽  
Vol 17 (6) ◽  
pp. 1876-1876 ◽  
Author(s):  
Parkash S. Gill ◽  
Anil Tulpule ◽  
Byron M. Espina ◽  
Suzanne Cabriales ◽  
Jocelyn Bresnahan ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Median Duration ◽  
Systemic Therapy ◽  
Kaposi's Sarcoma ◽  
Single Agent ◽  
Kaposi’S Sarcoma ◽  
Duration Of Response ◽  
Previously Treated ◽  
Prior Systemic Therapy ◽  
Grade 3

PURPOSE: Liposomal anthracyclines are the present standard treatment for advanced AIDS-related Kaposi's sarcoma (KS). No effective therapies have been defined for use after treatment failure of these agents. A phase II trial was thus conducted with paclitaxel in patients with advanced KS to assess safety and antitumor activity. MATERIALS AND METHODS: A regimen of paclitaxel at a dose of 100 mg/m2 was given every 2 weeks to patients with advanced AIDS-related KS. Patients were treated until complete remission, disease progression, or unacceptable toxicity occurred. RESULTS: Fifty-six patients with advanced AIDS-related KS were accrued. Tumor-associated edema was present in 70% of patients and visceral involvement in 45%. Forty patients (71%) had received prior systemic therapy; 31 of these were resistant to an anthracycline. The median entry CD4+ lymphocyte count was 20 cells/mm3 (range, 0 to 358). A median of 10 cycles (range, 1 to 54+) of paclitaxel was administered. Fifty-nine percent of patients showed complete (n = 1) or partial response (n = 32) to paclitaxel. The median duration of response was 10.4 months (range, 2.8 to 26.7+ months) and the median survival was 15.4 months. The main side effects of therapy were grade 3 or 4 neutropenia in 61% of patients and mild-to-moderate alopecia in 87%. CONCLUSION: Paclitaxel at 100 mg/m2 given every 2 weeks is active and well tolerated in the treatment of advanced and previously treated AIDS-related KS. The median duration of response is among the longest observed for any regimen or single agent reported for AIDS-related KS. Paclitaxel at this dosage and schedule is a treatment option for patients with advanced AIDS-related KS, including those who have experienced treatment failure of prior systemic therapy.

scholarly journals Bosutinib Apears to be Safe, with Low Cross Intolerance, in Patients Treated in 4th Line. Results of the Spanish Compassionate Use Program

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5523-5523 ◽  
Author(s):  
Valentín García-Gutiérrez ◽  
Begoña Maestro ◽  
Alejandra Martinez-Trillo ◽  
Jose Luis Lopez Lorenzo ◽  
Maria Luisa Martin Mateos ◽  
...  
Keyword(s):  
Side Effects ◽  
Pleural Effusion ◽  
Median Duration ◽  
Previous History ◽  
Safety Data ◽  
Compassionate Use ◽  
Vascular Events ◽  
Treatment Interruptions ◽  
Previously Treated ◽  
Grade 3

Abstract Second-generation TKIs have demonstrated efficacy and an acceptable tolerability in patients (pts) with chronic myeloid leukemia (CML); however, new data from so called “off target” side effects have been published. For example, serious concerns have been raised about cardiovascular (CV) events with ponatinib, and, in lesser degree with nilotinib (NI), impeding or difficulting the treatment in patients with previous CV risk factors. Besides, patients with previous history of pleural effusion or pulmonary hypertension should avoid dasatinib (DA) if possible. Bosutinib could be a good candidate for situations which preclude the use of other TKI’s. We have previously presented efficacy data of 29 patients treated with bosutinib in forth line. The aim of this study is to report safety data of heavily CML patients treated with bosutinib in 4th line. We have studied 30 pts previously treated with imatinib (IM), dasatinib and nilotinib and 5 pts previously treated with IM-DA or NI since 2012 under the Spanish Compassionate Use Program. Patient’s baseline characteristics and previous treatments are shown in table 1. We have classified patients in 2 groups regarding to investigator-driven cause of discontinuation: intolerant (INT) or resistant (RES). At the data cutoff on June 16, 2014, the median follow up was 11.47 months (range, 2.03-45.97 months). Median duration of BOS treatment across all cohorts was 9.23 months (range, 0.63-23.40 months). We observed no significant differences in terms of Index prognostic factors (Sokal, Hasford or Eutos), sex, median duration of TKIs treatment or comorbidities. However, patients with resistance where significantly older observed: 56 years vs. 67 years (p<0.05). Toxicity spectrum pre-BOS: Main reason for treatment discontinuation for each TKI was: treatment failure in the case of IM (14/35) and intolerance for both DA 16/34 and NI 13/31. Hematological (HEM) toxicities grade 3-4 with all TKIs were more common in RES pts, being dasatinib the one that showed the highest rate of grade 3-4 HEM toxicities. Non-HEM toxicities to all TKIs were significantly more frequent in INT than in RES pts (p<0.05). Most common grade 3-4 non-HEM toxicities were rash for IM (3/35), pleural effusion for DA (7/34) and vascular events for NI (3/31 Peripheral arterial disease (PAOD), 3/31 Ischemic heart disease (IHD)). Toxicity spectrum with BOS treatment: treatment interruptions were more frequent in INT than in RES pts 52% vs 25%, as well as dose reductions 78% vs 66% respectively. Grade 3-4 HEM toxicities were more common in RES than INT pts (41.6% vs 4.3% respectively). Non-HEM toxicities were also more frequent in RES pts than INT: diarrhea (50% vs 43%), rash (16% vs 8%), ALT or AST increase (25% vs 13%) abdominal pain (16% vs 4%), grade 3-4 non HEM toxicities were more frequent in RES than INT pts (41% vs 17%) (Diarrhea 16.7% vs 4.3%, AST/ALT increase: 16.7% vs 0%). None (0/12) vs 4/23 (17%) pts discontinued treatment due to toxicity in the RES vs. INT group respectively. Cross intolerance was extremely rare, of the 7 pts who had rash with IM, only 1 suffered rash with BOS. None pts had pleural effusion with BOS out of 15 who previously suffered with DA neither vascular events out of the 10 pts that previously suffered with NI. EFS by 20 months was 75% vs 50% for INT and RES patients. We have shown how in previously heavily pretreated CML patients, most of them in 4th line bosutinib has an excellent safety profile with no patients interrupting treatment due to side effects in previously intolerant patients. Importantly, rates of cross intolerance (namely CV, pleural and skin ) have also been very low. We conclude that Bosutinib is an excellent alternative also in patients who are left without a suitable treatment option. Table IM+NI-I +DA-R IMA+NI-R +DA-R IM+NI-I +DA-I IM+NI-R +DA-I IM+NI/DA TOTAL Pts, N(%) 2 (5.7) 7 (20) 15 (43) 6 (17) 5 (14) 35 (100) Age of diagnosis, med yr 61.0 46.7 54.7 53.8 58.7 54.2 Age of BOS initiation, med yr 74.7 61.5 64.6 64.8 65.5 63.8 Sokal index at diagnosis, N (High/intermidiate/low) 1/0/1 1/2/4 0/5/7 1/2/2 0/2/2 3/11/16 Time from first TKI to BOS, med yr 11.7 10.0 9.9 7.4 10.7 10.0 Duration of IM treatment, med, mo 63.3 33.1 26.6 21.4 78.2 27.2 Duration of DA treatment, med, mo 48.7 16.0 41.9 19.2 18.7 23.6 Duration of NI treatment, med ,mo 29.1 14.2 9.0 21.0 24.2 11.6 I:iIntolerance, R: resistant, med: median, yr: year, mo: months Disclosures García-Gutiérrez: Novartis: Consultancy; BMS: Consultancy; Pfizer: Consultancy; Ariad: Consultancy. Steegmann:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Ariad: Consultancy.

Endometriumkarzinom: Kombination aus Lenvatinib und Pembrolizumab zeigt Wirksamkeit unabhängig vom Mikrosatellitenstatus

2021 ◽  
pp. 1-2
Author(s):  
Sarah Matz
Keyword(s):  
Endometrial Carcinoma ◽  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Efficacy Analysis ◽  
Duration Of Response ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Prior Systemic Therapy ◽  
Grade 3

<b>Purpose:</b> Patients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort with advanced endometrial carcinoma receiving lenvatinib plus pembrolizumab in an ongoing phase Ib/II study of selected solid tumors. <b>Methods:</b> Patients took lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks, in 3-week cycles. The primary end point was objective response rate (ORR) at 24 weeks (ORRWk24); secondary efficacy end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Tumor assessments were evaluated by investigators per immune-related RECIST. <b>Results:</b> At data cutoff, 108 patients with previously treated endometrial carcinoma were enrolled, with a median follow-up of 18.7 months. The ORRWk24 was 38.0% (95% CI, 28.8% to 47.8%). Among subgroups, the ORRWk24 (95% CI) was 63.6% (30.8% to 89.1%) in patients with microsatellite instability (MSI)-high tumors (n = 11) and 36.2% (26.5% to 46.7%) in patients with microsatellite-stable tumors (n = 94). For previously treated patients, regardless of tumor MSI status, the median DOR was 21.2 months (95% CI, 7.6 months to not estimable), median PFS was 7.4 months (95% CI, 5.3 to 8.7 months), and median OS was 16.7 months (15.0 months to not estimable). Grade 3 or 4 treatment-related adverse events occurred in 83/124 (66.9%) patients. <b>Conclusion:</b> Lenvatinib plus pembrolizumab showed promising antitumor activity in patients with advanced endometrial carcinoma who have experienced disease progression after prior systemic therapy, regardless of tumor MSI status. The combination therapy had a manageable toxicity profile. <b>Trial registration:</b> ClinicalTrials.gov NCT02501096.

Final Results of a Phase II Trial of Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 920-920 ◽  
Author(s):  
Brad Pohlman ◽  
Ranjana Advani ◽  
Madeleine Duvic ◽  
Kenneth B. Hymes ◽  
Tanin Intragumtornchai ◽  
...  
Keyword(s):  
T Cell ◽  
Median Duration ◽  
Cell Lymphoma ◽  
Stage Iv ◽  
T Cell Lymphoma ◽  
Cutaneous Lesions ◽  
Stage Iv Disease ◽  
Duration Of Response ◽  
Post Infusion ◽  
Grade 3

Abstract Abstract 920 Background: Belinostat is a pan-HDAC inhibitor of the hydroxamate chemical class that is well-tolerated and has shown clinical activity. Methods: Open label, multicenter trial enrolling patients (pts) with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥ 1 prior systemic therapy. Pts received 1000 mg/m2 IV belinostat over 30 min on days 1 to 5 of a 3-wk cycle. Primary endpoint was objective response (OR) assessed by IWG criteria for PTCL and by SWAT (cutaneous lesions) and IWG criteria (non-cutaneous lesions) for CTCL. Pruritus in pts with CTCL was assessed using a 10-point scale; relief defined as reduction of pruritus score of ≥ 3 points in pts with baseline score ≥ 3. ECGs were monitored and reviewed centrally (pre-/ post-infusion ECGs on all treatment days in cycle 1, and pre-/ post-infusion ECGs on day 1 of subsequent cycles) to evaluate potential cardiac toxicity. Results: The study enrolled a total of 53 treated pts, including 20 and 29 evaluable pts with a diagnosis of PTCL and CTCL, respectively. The 20 pts with PTCL [10 PTCL-unspecified (PTCL-U), 3 anaplastic large cell lymphoma (ALCL), 3 angioimmunoblastic TCL (AITL), 3 NK/T-cell lymphoma, and 1 subcutaneous panniculitis-like TCL (SPTCL)] had received a median of 3 prior systemic therapies (range 1 – 10), and 40 % of them had stage IV disease. 5/20 (25%) PTCL pts responded with 2 CR (both in patients with PTCL-U) and 3 PR (PTCL-U, AITL, ALCL). The 5 responding pts had a median duration of response of 159+ days (range 1 – 504+). Additionally, SD was observed in 5 pts (2 PTCL-U, 2 NK/T-cell, and 1 ALCL) with median duration of SD of 109+ days (range 80 -185+). The 29 pts with CTCL [15 mycosis fungoides (MF), 7 Sezary syndrome (SS), 5 non MF/SS, 2 unclassified] had received a median of 1 prior skin directed therapies (range 0 – 4) and 3 prior systemic therapies (range 1 – 9), and 55 % of them had stage IV disease. 4/29 (14%) CTCL pts responded with 2 CR (ALCL, MF) and 2 PR (MF, SS). The 4 responding pts had a median duration of response of 273 days (range 48 - 469+). Importantly, time to response was short with a median of 16 days (range 14-35). In addition, SD was observed in 17 pts (10 MF, 3 SS, 2 non MF/SS, 2 unclassified) with current duration of up to 127 days. Pruritus relief (score reduction ≥ 3) was seen in 7 of 14 pts with significant baseline pruritis. Median time to pruritus relief was also short, 16 days (range 7-45). Hematological toxicity was minimal without any grade 4 events (shift from baseline) and only one pt each experiencing grade 3 neutropenia and grade 3 thrombocytopenia, respectively. No grade 3 QTcF prolongation was detected in more than 700 ECGs. Four grade 3/4 drug-related AEs were reported: pruritis, rash/erythema, edema, and adynamic ileus. Conclusions: Belinostat monotherapy is safe, well tolerated, and efficacious in pts with recurrent/refractory T-cell lymphoma with durable remissions in both CTCL and PTCL. These results are the basis for a pivotal study with belinostat monotherapy in pts with PTCL. Disclosures: Advani: Seattle Genetics, Inc.: Research Funding. Duvic:Topotarget: research support for conduct of clinical trial. Fagerberg:TopoTarget A/S: Employment, Equity Ownership. Foss:Eisai : Speakers Bureau.

Long-Term Outcomes and Safety of Continuous Lenalidomide Plus Dexamethasone (Len+Dex) Treatment in Patients (Pts) with Relapsed or Refractory Multiple Myeloma (RRMM)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2929-2929 ◽  
Author(s):  
Meletios Athanasios Dimopoulos ◽  
Mohamad Hussein ◽  
Arlene S Swern ◽  
Donna M. Weber
Keyword(s):  
Dose Reduction ◽  
Median Duration ◽  
Cox Regression ◽  
Incidence Rates ◽  
Long Term Outcomes ◽  
Cox Regression Analysis ◽  
Β2 Microglobulin ◽  
Grade 3

Abstract Abstract 2929 Background: Two pivotal phase 3 trials (MM-009 and MM-010) randomized 704 pts to assess Len+Dex vs placebo plus dexamethasone (Dex) in RRMM. The results demonstrated the significant overall survival (OS) benefit of Len+Dex vs Dex (38.0 vs 31.6 mos; p =.045) despite crossover of 48% of Dex pts to the Len+Dex arm at unblinding or progression (Dimopoulos MA et al. Leukemia 2009;23 :2147-52). This is an analysis of the long-term outcomes and safety of continuous Len+Dex treatment. Methods: This retrospective analysis pooled pts treated with Len+Dex in MM-009 and MM-010, with a median follow-up of 48 mos for surviving pts. A subset of pts with progression-free survival (PFS) of ≥ 2 yrs was selected. Prognostic factors for PFS within this subgroup of pts were identified by incorporating all baseline covariates with a univariate p <.15 into multivariate Cox regression analyses, and all possible models were fitted using SAS 9.2. Adverse event (AE) management and dosing for pts with PFS ≥ 2 yrs was compared with that for all pts treated with Len+Dex in order to evaluate if differences in pt management could contribute to better clinical outcomes. Incidence rates for AEs were calculated using person-yrs of follow-up. Data from pts who received Len+Dex in MM-009 (up to July 23, 2008) and MM-010 (up to March 2, 2008) were included in this analysis. Results: Among all pts treated with Len+Dex (N = 353), a total of 64 pts (18%) achieved PFS ≥ 2 yrs. For these 64 pts, median age was 61 yrs (range 33–81 yrs), 48% received > 1 prior therapy, and 57% had β2-microglobulin levels of ≥ 2.5mg/L. All these pts achieved a ≥ partial response (PR), including 67% with a ≥ very good PR and 50% with a complete response. Median time to first response was 2.8 mos (range 1.9–18.2 mos) which is comparable to that of all pts treated with Len+Dex. Median duration of response was not reached vs 15.5 mos, respectively. With median follow-up of 49 mos, the 3-yr OS is 94% (95% confidence interval [CI] 88.06–99.94). In a multivariate Cox regression analysis, shorter PFS was predicted with higher baseline β2-microglobulin level (hazard ratio [HR] 1.07; 95% CI 1.02–1.12) and lower hemoglobin (HR 0.91; 95% CI 0.84–0.99), as well as a higher number of prior therapies (HR 1.18; 95% CI 1.02–1.37). The median duration of treatment was longer among pts with PFS ≥ 2 yrs vs all pts treated with Len+Dex (46.2 mos [range 11.3–58.3] vs 9.8 mos [range 3.8–24], respectively). A higher proportion of these pts had a dose reduction within 12 mos after start of therapy vs all pts treated with Len+Dex (57% vs 24%, respectively). Dex dose was reduced in 27% of pts with PFS ≥ 2 yrs. Among pts without Len dose reduction, 31% had Dex dose reduction within the first 4 cycles. Granulocyte colony-stimulating factor was administered for the management of neutropenia in 39% of pts with PFS ≥ 2 yrs vs 25% of all pts treated with Len+Dex. Low discontinuation rates due to AEs were observed in both groups (12.5% vs 18.7%, respectively). The incidence rates per 100 person-yrs for grade 3–4 AEs among pts with PFS ≥ 2 yrs vs all pts treated with Len+Dex (N = 353) were, respectively: neutropenia (14.9 vs 29), febrile neutropenia (0.9 vs 2.3), thrombocytopenia (2.6 vs 10.2), anemia (4.4 vs 9.5), infection (11.8 vs 20.9), deep vein thrombosis/pulmonary embolism (2.2 vs 8.9), fatigue (2.2 vs 5.5), neuropathy (1.8 vs 3.4), and gastrointestinal disorders (5.3 vs 9.7). The incidence rates per 100 person-yrs for second primary malignancies (SPMs) were similar to that of all pts treated with Len+Dex, respectively: myelodysplastic syndromes (0 vs 0.4), solid tumor (1.8 vs 1.3), and non-melanoma skin cancer (2.3 vs 2.4). These rates are comparable to those expected in people aged > 50 yrs generally (1.4 per 100 person-yrs) (Altekruse SF et al. SEER Cancer Statistics Review, 1975–2007). Conclusions: Long-term continuous therapy with Len+Dex has demonstrated efficacy and is generally well tolerated in pts with RRMM. Overall, 18% of patients treated with Len+Dex achieve a PFS of > 2 yrs. No increase in SPMs was observed with long term Len+Dex therapy. With appropriate AE management, the incidence rates of grade 3–4 AEs remain low. This analysis demonstrates the value of AE management and the need for appropriate dose-adjustment to maintain tolerability, allowing pts to remain on therapy for maximal benefit. Disclosures: Dimopoulos: Celgene Corporation: Consultancy, Honoraria. Hussein:Celgene Corporation: Employment. Swern:Celgene Corporation: Employment. Weber:Celgene Corporation: Honoraria, Research Funding.

A Phase II Open-Label, Multi-Center Study of Anti-CCR4 Monoclonal Antibody Mogamulizumab (KW-0761) in Patients with Previously Treated Peripheral T-Cell Lymphoma(PTCL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1763-1763 ◽  
Author(s):  
Pier Luigi Zinzani ◽  
Bertrand Coiffier ◽  
John Radford ◽  
Dolores Caballero ◽  
Paul Fields ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Median Number ◽  
Advisory Board ◽  
Japanese Study ◽  
Duration Of Response ◽  
Previously Treated ◽  
Grade 3

Abstract Background CC chemokine receptor 4 (CCR4) is the receptor for macrophage-derived chemokine (MDC/CCL22) and thymus activation-regulated chemokine (TARC/CCL17). CCR4 is expressed on tumour cells in approximately 30-65% of patients with PTCL (Ogura, 2014). PTCL-NOS patients who are CCR4 positive have been reported to have a poorer prognosis compared to CCR4 negative patients (Ishida T CCR 2004). Mogamulizumab (KW-0761) is a defucosylated, humanized, IgG1 Mab with enhanced antibody dependent cellular cytotoxicity, that binds to CCR4. Mogamulizumab was evaluated in both phase 1 and 2 trials in Japanese patients. A phase II trial in PTCL and cutaneous T-cell lymphoma (CTCL) patients (Ogura, 2014) reported an overall response rate (ORR) of 35% in patients who relapsed after last systemic therapy (ORR was 34% in PTCL), leading to its approval in Japan in patients with previously treated CTCL and PTCL, in addition to its first indication, previously treated adult T-cell leukemia-lymphoma. Here we report the preliminary results of a European phase II trial of mogamulizumab in patients with relapsed/refractory PTCL. Methods A multi-center phase II study of mogamulizumab monotherapy was conducted to determine efficacy, safety and immunogenicity in patients with CCR4+ PTCL. The primary endpoint was ORR and secondary endpoints included duration of response, progression-free survival (PFS) and overall survival (OS). At least 34 evaluable patients were needed to detect a significant improvement over 15% assuming 80% power and a 0.0240 alpha significance level (assumes 35% ORR for alternative). Patients received mogamulizumab once weekly for 4 weeks and subsequently once every 2 weeks until progressive disease (PD) or unacceptable toxicity at a dose of 1.0 mg/kg. Responses were assessed every 8 weeks according to IWG criteria (Cheson et al 2007). Results Based on a preliminary analysis of the data, a total of 38 patients received at least one administration of mogamulizumab and were evaluable for safety analysis; (Male/female 23/15 ;Median age 58.5 years (range 19-87)). Three patients are still ongoing in the study (1 complete response (CR) and 2 stable disease (SD)). ECOG performance status at baseline was 0 (32%); 1 (29%); 2 (39%) and 92% of patients had stage III (32%) or IV (61%) disease. The median number of prior treatments was 2 (range 1-8). Only 17 patients (49%) responded to the last treatment administered prior to study entry. The median number of mogamulizumab administrations was 6 (range 1-32). The majority of adverse events (AEs) were CTCAE grade 1-2. Skin rash related to drug was observed in 32% of patients (12/38) and related AEs > grade 3 occurred in 32% (12) of patients. Infusion related reactions occurred in 3 patients (2 were CTCAE grade 2 and 1 was grade 3). Thirty-five patients were evaluable for efficacy. The ORR rate was 11% and the stable disease rate was 34% with a SD or better rate of 46%. The response by histological subtype is specified in the table below. The median duration of response (including SD) is 2.9 months. The median PFS is 2.1 months. Two patients (ALCL-ALK-neg and PTCL-NOS) proceeded to allogeneic SCT. Although the ORR in this study was less than seen in the Japanese study, the PFS was comparable. There were differences in patient population/study conduct between the Japanese study and this study, respectively, which included: inclusion of only relapsed patients (100% vs 49%), ECOG PS 2 (0% vs 39%) and response assessments (after 4 and 8 weeks versus 8 weekly from week 8). Conclusions Based on preliminary data, mogamulizumab demonstrates a SD or better rate of 46% and an ORR of 11% with an acceptable safety profile in this phase II study of heavily pre-treated relapsed/refractory PTCL patients. TableBest Overall Response by Histological subtypeNo of subjectsCR/PR n (%)SDn (%)>SD n (%)PTCL-NOS152* (13%)6 (40%)8 (53%)AITL122 (17%)3 (25%)5 (42%)TMF301 (33%)1 (33%)ALCL-ALK neg402 (50%)2 (50%)ALCL-ALK pos1000Efficacy Evaluable Subjects354 (11%)12 (34%)16 (46%) *One patient had CR by CT scan but did not have bone marrow done for confirmation of CR Disclosures Zinzani: Sandoz: Consultancy; Celgene International Sàrl: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; MundiPharma International Ltd: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Pfizer Inc: Advisory Board Other, Honoraria, Speakers Bureau; Takeda Pharmaceutical Company Limited: Advisory Board Other, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Advisory Board Other, Honoraria; GlaxoSmithKline: Advisory Board, Advisory Board Other, Honoraria; Gilead: Advisory Board, Advisory Board Other; Bayer AG: Advisory Board Other, Consultancy. d'Amore:CTI Life Sciences: Speakers Bureau; Mundipharma: Speakers Bureau; Takeda/Seattle Genetics : Speakers Bureau; Sanofi-Aventis: Research Funding; Amgen: Research Funding; Roche: Research Funding; Kyowa-Kirin: Advisory Board Other. Haioun:Roche: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Morschhauser:Genentech: Honoraria; Bayer: Honoraria; Spectrum: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria.

Impact of bevacizumab dose reduction on clinical outcomes for patients treated on the Eastern Cooperative Oncology Group’s Study E3200

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3538-3538 ◽  
Author(s):  
B. J. Giantonio ◽  
P. J. Catalano ◽  
P. J. O’Dwyer ◽  
N. J. Meropol ◽  
A. B. Benson
Keyword(s):  
Dose Reduction ◽  
Progression Free Survival ◽  
Free Survival ◽  
Hazard Ratios ◽  
Previously Treated ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Colorectal Cancer Patients ◽  
Dose Modifications ◽  
Dose Reductions

3538 Background: E3200 demonstrated improved survival (OS) for previously treated metastatic colorectal cancer patients who received second-line therapy with bevacizumab (10 mg/kg) in combination with FOLFOX4. Dose reductions of bevacizumab to 5 mg/kg were allowed for: hypertension, bleeding and thrombosis of ≤ grade 2; proteinuria of > 2 grams/24 that resolved to <0.5 grams/24hrs; liver function abnormalities ≥ grade 3 that resolved to ≤ grade 1. Methods: Data on dose modifications of bevacizumab were obtained from a post-study survey of participating institutions for all participants. Median OS and progression-free survival (PFS) were determined based upon a dose reduction any time during treatment. Hazard ratios (HR) for OS and PFS were stratified by number of cycles (1–5, 6–10, 11+) to adjust for the time-varying nature of dose reductions. Results: Surveys were received on 84% of E3200 patients treated with bevacizumab. Dose reductions of bevacizumab were performed in 134 of 240 (55.8%) patients treated with FOLFOX + bevacizumab (Arm A) and 77 of 205 (37.6%) patients treated with bevacizumab alone (Arm C). The average number of cycles of bevacizumab administered at a dose reduction for Arm A is 42% and for Arm C is 52%. Conclusions: OS and PFS on E3200 were not compromised for patients who underwent dose reductions of bevacizumab. [Table: see text] [Table: see text]

Ramucirumab (R) plus pembrolizumab (P) in treatment naive and previously treated advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: A multi-disease phase I study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4046-4046 ◽  
Author(s):  
Ian Chau ◽  
Johanna C. Bendell ◽  
Emiliano Calvo ◽  
Rafael Santana-Davila ◽  
Hendrik-Tobias Arkenau ◽  
...  
Keyword(s):  
Median Duration ◽  
Gastroesophageal Junction ◽  
Survival Rates ◽  
Kidney Injury ◽  
Primary Objective ◽  
Treatment Naïve ◽  
Previously Treated ◽  
Grade 3 ◽  
Ecog Ps ◽  
Clinical Trial Information

4046 Background: Angiogenesis and immunosuppression are hallmarks of tumor growth. This is the first study to combine R (anti-VEGFR2) with P (anti-PD-1) to simultaneously target both processes in the tumor microenvironment. Methods: Ongoing, multi-cohort, phase 1a/b trial enrolled pts with G/GEJ adenocarcinoma, measurable disease, ECOG PS 0-1, previously treated (Cohorts A and B) or untreated (Cohort A2) for advanced disease. PD-L1 was positive (tumor proportion score [TPS] ≥1%) or negative (TPS < 1%) using the DAKO PD-L1 22C3 IHC pharmDx assay. R was administered at 8 mg/kg on Days 1&8 (Cohorts A and A2) or 10 mg/kg on Day 1 (Cohort B) with P 200 mg on Day 1 q3W. Primary objective- assess safety and tolerability of R+P; preliminary efficacy will be examined. Results: As of 21-Nov-2016, 41 previously treated G/GEJ pts were enrolled. Median age was 58 y, 76% male, 66% had ECOG PS of 1, 46% were PD-L1+, and 59% received study treatment as third or subsequent line. Median duration on therapy was 2.8 mo and 4.1 mo for A and B, respectively. Overall, 33 (80%) pts experienced a treatment-related AE (TRAE) and similar between cohorts A and B. Ten (24%) pts experienced grade 3-4 TRAEs, most commonly colitis (7%) and hypertension (7%). One treatment-related death occurred (pneumonitis and pulmonary sepsis). Responses occurred in 3 (7%) pts with 46% disease control rate (DCR). Progression-free and overall survival rates at 6 mo were 22.4 % (95% CI, 9.8-38.0) and 51.2% (95% CI, 33.9-66.1) respectively. Nine (22%) pts remain on treatment. Eighteen of 25 planned treatment naïve G/GEJ pts were enrolled. Median age was 70 yr, 83% male, 56% had ECOG PS of 0, and PD-L1 status is pending. Median duration on therapy was 2.1 mo. Twelve (67%) pts experienced a TRAE. Grade 3 TRAEs occurred in 5 (28%) pts (hypertension [n = 3], diarrhea, and acute kidney injury). No grade 4-5 events occurred. Preliminary efficacy data showed 3 (17%) pts responded with 50% DCR. Median PFS is immature and 89% of pts remain on treatment. Conclusions: R+P generated no new safety signals and demonstrated encouraging antitumor activity in treatment naïve and previously treatedadvanced G/GEJ adenocarcinoma. Clinical trial information: NCT02443324.

Phase II study of the FGFR inhibitor AZD4547 in previously treated patients with FGF pathway-activated stage IV squamous cell lung cancer (SqNSCLC): LUNG-MAP sub-study SWOG S1400D.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9055-9055 ◽  
Author(s):  
Charu Aggarwal ◽  
Mary Weber Redman ◽  
Primo Lara ◽  
Hossein Borghaei ◽  
Philip C. Hoffman ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Grade 5 ◽  
Duration Of Response ◽  
Secondary Endpoints ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3

9055 Background: LungMAP is a National Clinical Trials Network umbrella trial for previously-treated SqNSCLC. S1400D is a phase II biomarker-driven therapeutic sub-study evaluating the FGFR inhibitor AZD4547 in patients (pts) with FGFR positive chemo-refractory SqNSCLC. Methods: Eligible pts had tumor FGFR alteration and/or mutation by next generation sequencing (Foundation Medicine), measurable disease, Zubrod PS 0-2, progression after 1 line of systemic therapy, and adequate end organ function. Receipt of prior immunotherapy was allowed. Eligible pts received AZD4547 80 mg bid orally. Primary endpoint was overall response rate (ORR) by RECIST; secondary endpoints included progression-free survival (PFS) and duration of response (DoR). Originally designed as a randomized trial of AZD4547 versus docetaxel, it was redesigned to be a single arm AZD4547 trial with the emergence of immunotherapy as standard 2ndline therapy. Forty pts were required to rule out an ORR of < = 15% if the true ORR was > 35% (90% power, alpha 0.05). Results: 93 pts (13% of pts screened on S1400) were assigned to S1400D; 43 were enrolled with 28 receiving AZD4547. Pt characteristics: median age 66.3 y (49-88), female (n = 8, 29%), & Caucasian (n = 25; 89%). Biomarker profile: FGFR1 amplification (n = 38; 86%); FGFR3 S249C (n = 4; 9%); FGFR3 amplification (n = 3; 7%); and FGFR3 fusion (n = 2; 5%). Nine pts (26%) had more than one biomarker alteration. The study was closed at interim analysis for futility in October 2016. Treatment related Grade 3 AEs were seen in 5 pts (dyspnea, fatigue, hyponatremia, lung infection & retinopathy); 1 pt had Grade 4 sepsis. There were no Grade 5 AEs. Median follow up among alive pts was 4.3 months (mos). Of 25 response evaluable pts, one with FGFR3 S249C had unconfirmed PR (4%, 95% CI 1-20%) with DoR of 1.5 mos. Median PFS was 2.7 mos (95% CI 1.4 - 4.3 mos). Conclusions: This is the first Phase II trial to evaluate AZD4547 as a targeted approach in pts with previously treated FGFR-altered SqNSCLC. AZD4547 had an acceptable safety profile but minimal activity in this biomarker-enriched cohort. Evaluation of other targeted agents in LUNG-MAP is currently ongoing. Clinical trial information: NCT02965378.

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