Randomized phase I/II trial of pembrolizumab with and without radiotherapy for metastatic non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9104-9104 ◽  
Author(s):  
James William Welsh ◽  
Hari Menon ◽  
Chad Tang ◽  
Vivek Verma ◽  
Mehmet Altan ◽  
...  
Keyword(s):  
Phase I ◽  
Stereotactic Body Radiation Therapy ◽  
Response Rate ◽  
Metastatic Nsclc ◽  
Field Response ◽  
Grade 3 ◽  
Nsclc Patients ◽  
To Receive ◽  
Clinical Trial Information

9104 Background: We present findings of a randomized phase I/II trial studying PD-1 blockade with and without radiotherapy to lung lesions in patients with metastatic NSCLC. Methods: Patients with metastatic NSCLC were randomized to receive pembrolizumab with or without lung-directed radiotherapy (RT). RT referred to stereotactic body radiation therapy (SBRT, 50 Gy in 4 fractions or 70 Gy in 10 fractions) or traditional fractionation (45 Gy in 15 fractions). Pembrolizumab (200mg IV) was started on day 1 and given every 3 weeks for up to sixteen cycles. The primary endpoint was out-of-field response rate (RR), which refers to complete (CR) or partial response (PR) per irRC criteria. Results: Of 124 enrolled patients, 103 received treatment, 5 withdrew consent, 15 screen failures, and 1 was not financially cleared. Twenty-one patients completed 16 cycles of pembrolizumab; 16 patients received SBRT and 20 received traditional RT. Seven patients received salvage RT after progression on pembrolizumab alone and 15 patients received RT six months before starting the trial. In the combined-modality arm, there were 2 grade 4 toxicities and 9 grade 3 toxicities related to treatment. In the pembrolizumab arm, there were zero grade 4 toxicities and five grade 3 toxicities. At the present time, 72 patients were evaluable for response, 36 in both arms; median follow-up was 15.4 months (range: 1.4-125.2 months). RR for out-of-field lesions was 22% and 25% for the pembrolizumab + RT vs pembrolizumab respectively (p = 1.00); median PFS was 10.9 months (95% CI, 8.1-15.3 months) and 8.4 months (95% CI, 3.9-17.1 months) respectively (p = 0.83). When comparing the SBRT vs traditional fractionation sub-cohorts, non-irradiated RR was 38% and 10% respectively (p = 0.10); median PFS was 21.1 and 6.8 months respectively (p = 0.03). Within the pembrolizumab arm, comparing patients who received prior RT vs those that did not, RR was 33% and 19% respectively (p = 0.26). Conclusions: RT, while safe, did not increase the out-of-field response rate in NSCLC patients treated with pembrolizumab. Exploratory analysis suggests responses may be enhanced by SBRT, but not traditional fractionation, which warrants further investigation. Clinical trial information: NCT02444741.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1874-1874 ◽  
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Peter Anglin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Oral Cyclophosphamide ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 1874 Poster Board I-899 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen in relapsed/refractory multiple myeloma (MM) patients (pts), with an overall response rate of 60.6% and median time to progression (TTP) of 13.4 months (Dimopoulos MA, et al, Leukemia 2009 Jul 23 [Epub ahead of print]). Oral cyclophosphamide and prednisone is an older regimen with excellent patient tolerance, and we sought to enhance the efficacy of lenalidomide by adding oral cyclophosphamide and prednisone in this phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15; lenalidomide on days 1–21; and prednisone 100 mg every other day in a 28 day cycle. ASA 81 mg/day was given to all pts as DVT prophylaxis. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2009, 31 pts with relapsed/refractory MM who had not previously received lenalidomide were entered onto study. Median age was 61 (40–78) years and 61% were male. Immunoglobulin subtype was IgG in 19 pts (61%), IgA in 8 pts (26%) and light chain only in 4 pts (13%). Median number of prior regimens was 2 (1–5) and 28 pts had undergone previous ASCT, including double transplants in 6 pts. Prior therapy included thalidomide in 9 (29%) and bortezomib in 15 (48%). FISH cytogenetics were available in 13 pts; one had 13q deletion but none had t(4;14) or p53 deletion. At the time of protocol entry, median β 2-microglobulin level was 246 (92–767) nm/L, albumin 39 (34–48) g/L, creatinine 83 (50–126) μmol/L, platelet count 230 (75–337) × 109/L and ANC 2.5 (1.1–6.1) x 109/L. Protocol treatment is summarized in Table 1. Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities included thrombocytopenia in 5 pts (16%) and neutropenia in 9 pts (29%). These were managed with dose reduction and/or growth factor support. Four episodes of febrile neutropenia occurred. Other grade 3–4 non-hematologic toxicities included abdominal pain/bacteremia in 1 pt in cohort 1; hypokalemia in 1 pt in cohort 2; and DVT in 2 pts, dizziness in 2 pts and fatigue in 1 pt in cohort 3. Using the International uniform response criteria (Durie BG, et al, Leukemia 2006; 20:1467–1473), the best response was documented at a median of 6 (1–5) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (5 CR, 9 VGPR, 9 PR, 1 MR and 1 stable disease). At a median follow-up (F/U) of 12 (8–21) months, 20 pts remain on study, 2 have withdrawn and 9 pts have progressed at a median of 9 (4–13) months; only 1 one has died (due to MM). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with minimal toxicity; 2) the overall response rate (CR + VGPR + PR) in 31 pts to date is 93%; 3) at a median F/U of 1 year, only 9 pts (29%) have progressed; 4) longer follow-up is required to assess the TTP and survival of the CPR regimen. Disclosures: Reece: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Lenalidomide in combination with drugs other than dexamethasone. Anglin:Celgene: Honoraria. Chen:Celgene: Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Mikhael:Celgene: Honoraria. Trudel:Celgene: Honoraria.

First-line (1L) avelumab treatment in patients (pts) with metastatic Merkel cell carcinoma (mMCC): Preliminary data from an ongoing study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9530-9530 ◽  
Author(s):  
Sandra P. D'Angelo ◽  
Jeffrey Russell ◽  
Jessica Cecile Hassel ◽  
Celeste Lebbe ◽  
Bartosz Chmielowski ◽  
...  
Keyword(s):  
Safety Profile ◽  
Response Rate ◽  
Objective Response ◽  
Durable Response ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Related Reaction ◽  
Unacceptable Toxicity ◽  
Clinical Trial Information

9530 Background: MCC is a rare, aggressive skin cancer. Avelumab is a fully human anti–PD-L1 antibody. In a phase 2 study in pts with distant mMCC who progressed after prior chemotherapy (JAVELIN Merkel 200; NCT02155647), avelumab showed a manageable safety profile and durable responses, including an objective response rate (ORR) of 31.8%, estimated 6-month durable response rate of 29%, and 6-month overall survival rate of 69%. Here, we report preliminary results from a separate cohort of pts with chemotherapy-naïve mMCC enrolled in the same study. Methods: Eligible pts with mMCC and no prior systemic treatment for metastatic disease received avelumab 10 mg/kg Q2W until confirmed progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 weeks (RECIST v1.1). Adverse events (AEs) were assessed by NCI CTCAE v4.0. Results: As of Dec 30, 2016, 29/112 planned pts had been enrolled. Median age was 75.0 years (range 47–87). Median treatment duration was 8.1 weeks (range 2.0–37.9). Of 16 pts with ≥3 months of follow-up, unconfirmed ORR was 68.8% (95% CI 41.3–89.0) with CR in 18.8%; confirmed ORR was 56.3% (95% CI 29.9–80.2; 1 unconfirmed PR with discontinuation). Of 25 pts with ≥6 weeks of follow-up, unconfirmed ORR was 64.0% (95% CI 42.5–82.0). All responses were ongoing at last follow-up, including in 5/5 pts with ≥6 months of follow-up (potential to confirm responses). 20/29 pts (69.0%) had a treatment-related AE (TRAE), including grade 3–4 TRAE in 5 pts (17.2%). TRAEs led to discontinuation in 5 pts (17.2%): 2 pts with infusion-related reaction, and 1 pt each with elevated AST and ALT, cholangitis, and paraneoplastic syndrome. There were no treatment-related deaths. 21/29 pts (72.4%) remain on treatment. Conclusions: In initial results from a cohort of chemotherapy-naïve pts with mMCC, avelumab was associated with early responses and a manageable safety profile, consistent with findings for second-line or later avelumab treatment in a previous cohort. These results suggest that responses mature to become durable and the use of 1L avelumab may increase the probability of response vs later-line treatment. Enrollment and follow-up in this 1L cohort are ongoing. Clinical trial information: NCT02155647.

IMpower150: Analysis of efficacy in patients (pts) with liver metastases (mets).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9012-9012 ◽  
Author(s):  
Mark A. Socinski ◽  
Robert M. Jotte ◽  
Federico Cappuzzo ◽  
Tony S. K. Mok ◽  
Howard West ◽  
...  
Keyword(s):  
Efficacy And Safety ◽  
Wild Type ◽  
Poor Prognostic Factor ◽  
Risk Of Death ◽  
Metastatic Nsclc ◽  
New Treatment ◽  
Metastatic Sites ◽  
To Receive ◽  
Clinical Trial Information

9012 Background: Atezolizumab (atezo) + bevacizumab (bev) + chemo (carboplatin + paclitaxel [CP]; ABCP) showed improved PFS and OS vs bev + CP (BCP) in pts with chemo-naive NSCLC (IMpower150). Benefit with ABCP vs BCP extended to key subgroups, including pts with baseline (BL) liver mets, which is a poor prognostic factor in metastatic NSCLC. Similar outcomes were not seen with atezo + chemo (IMpower150 [atezo + CP; ACP]; IMpower130; IMpower132), suggesting that the addition of bev to atezo + chemo is important for conferring clinical benefit in these pts. Here we further explore characteristics and responses of pts with BL liver mets in IMpower150. Methods: 1202 ITT pts were randomized 1:1:1 to receive ABCP, ACP or BCP. Doses were: A, 1200 mg; B, 15 mg/kg; C, AUC 6 mg/mL/min; P, 200 mg/m2. Coprimary endpoints were OS and investigator-assessed PFS in ITT–wild-type pts. Exploratory analyses included efficacy and safety in pts with liver mets. Results: The data capture ≥ 20-mo follow-up in ITT pts (data cutoff: Jan 22, 2018). 162 pts had BL liver mets (ABCP, n = 52; ACP; n = 53; BCP, n = 57), with a median of 3 metastatic sites and median BL tumor SLD of 109 mm (range, 10-249). BL characteristics in these pts were generally balanced across study arms. PFS and OS were improved with ABCP vs BCP (Table). Gr 3-4 treatment-related AEs occurred in 52.1%, 36.5% and 54.5% of pts with liver mets in the ABCP, ACP and BCP arms, respectively. Conclusions: ABCP reduced the risk of death in pts with liver mets by 48% vs BCP and may represent an important new treatment option for this population. Clinical trial information: NCT02366143. [Table: see text]

Update on KEYNOTE-199, cohorts 1-3: Pembrolizumab (pembro) for docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 104-104 ◽  
Author(s):  
Emmanuel S. Antonarakis ◽  
Josep M. Piulats ◽  
Marine Gross-Goupil ◽  
Jeffrey C. Goh ◽  
Ulka N. Vaishampayan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Response Rate ◽  
Phase 2 ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Phase 2 Study ◽  
Previously Treated ◽  
Grade 3 ◽  
Clinical Trial Information

104 Background: The KEYNOTE-199 multicohort phase 2 study (NCT02787005) showed that pembro monotherapy has antitumor activity and acceptable safety in patients (pts) with mCRPC previously treated with a next-generation hormonal agent (NHA) and docetaxel in cohort 1 (C1) (RECIST-measurable, PD-L1+ disease), C2 (RECIST-measurable, PD-L1− disease), and C3 (bone-predominant disease, irrespective of PD-L1). Updated results with additional follow-up for C1-3 are presented. Methods: Pts previously received ≥1 NHAs and 1 or 2 chemotherapies, including docetaxel. Pts received pembro 200 mg Q3W for 35 cycles or until progression or intolerable toxicity. Primary end point was ORR. Key secondary end points were DCR, DOR, PSA (≥50%) response rate, rPFS, OS, and safety. Results: Of 258 pts enrolled (C1=133; C2=67; C3=58), 6 completed (C1=4; C3=2) and 252 discontinued (C1=129; C2=67; C3=56) therapy, primarily due to progression (C1=106; C2=61; C3=45). Median follow-up was 9.6 mo (C1, 9.5; C2, 7.9; C3, 14.2). ORR (95% CI) for pts with measurable disease was 6% (2.6-11.5) in C1 and 3% (0.4-10.4) in C2 (Table; includes other efficacy results). Treatment-related AEs of any grade/grade 3-5 occurred in 57%/16% in C1, 60%/15% in C2, and 71%/17% in C3. 1 pt in each cohort died of a treatment-related AE (C1, sepsis; C2, unknown; C3, immune-related pneumonitis). Conclusions: With additional follow-up, pembro monotherapy continued to show antitumor activity and disease control in pts with RECIST-measurable and bone-predominant mCRPC previously treated with both NHA and docetaxel. Pts experienced durable responses. Safety was consistent with the known safety profile of pembro. Clinical trial information: NCT02787005. [Table: see text]

Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: Updated Follow-Up and Improved Survival

2014 ◽  
Vol 32 (7) ◽  
pp. 634-640 ◽  
Author(s):  
Antonio Palumbo ◽  
Sara Bringhen ◽  
Alessandra Larocca ◽  
Davide Rossi ◽  
Francesco Di Raimondo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Response Rate ◽  
Complete Response Rate ◽  
Progression Free Survival ◽  
Complete Response ◽  
Free Survival ◽  
Grade 3 ◽  
To Receive

Purpose Bortezomib-melphalan-prednisone (VMP) has improved overall survival in multiple myeloma. This randomized trial compared VMP plus thalidomide (VMPT) induction followed by bortezomib-thalidomide maintenance (VMPT-VT) with VMP in patients with newly diagnosed multiple myeloma. Patients and Methods We randomly assigned 511 patients who were not eligible for transplantation to receive VMPT-VT (nine 5-week cycles of VMPT followed by 2 years of VT maintenance) or VMP (nine 5-week cycles without maintenance). Results In the initial analysis with a median follow-up of 23 months, VMPT-VT improved complete response rate from 24% to 38% and 3-year progression-free-survival (PFS) from 41% to 56% compared with VMP. In this analysis, median follow-up was 54 months. The median PFS was significantly longer with VMPT-VT (35.3 months) than with VMP (24.8 months; hazard ratio [HR], 0.58; P < .001). The time to next therapy was 46.6 months in the VMPT-VT group and 27.8 months in the VMP group (HR, 0.52; P < .001). The 5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P = .01). Survival from relapse was identical in both groups (HR, 0.92; P = .63). In the VMPT-VT group, the most frequent grade 3 to 4 adverse events included neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). All of these, except for thrombocytopenia, were significantly more frequent in the VMPT-VT patients. Conclusion Bortezomib and thalidomide significantly improved OS in multiple myeloma patients not eligible for transplantation.

Afatinib monotherapy in patients with metastatic squamous cell carcinoma of the lung progressing after erlotinib/gefitinib (E/G) and chemotherapy: Interim subset analysis from a phase III trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7558-7558 ◽  
Author(s):  
Joo-Hang Kim ◽  
Francesco Grossi ◽  
Filippo De Marinis ◽  
Manuel Cobo ◽  
James Chih-Hsin Yang ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Treatment Options ◽  
Phase Iii ◽  
Open Label ◽  
Metastatic Nsclc ◽  
Erbb4 Receptor ◽  
Grade 3 ◽  
Patient Enrolment ◽  
Nsclc Patients ◽  
To Receive

7558 Background: Patients with squamous NSCLC have limited treatment options. For those deriving benefit from EGFR TKIs, it is unclear whether sustained ErbB family blockade offers benefit upon progression. We evaluated afatinib, an irreversible blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor tyrosine kinases, in patients with metastatic NSCLC who had failed chemotherapy and E/G. Here we describe a pre-specified analysis of those with squamous histology in Part A. Methods: This randomized Phase III, open-label, multi-center trial enrolled patients with pathologically confirmed metastatic NSCLC after failing ≥1 line of cytotoxic chemotherapy and E/G. In Part A, patients received oral afatinib 50 mg until disease progression. Those with clinical benefit (≥12 wks) who progressed were eligible to receive afatinib plus paclitaxel or investigator’s choice chemotherapy (Part B). Primary endpoint was PFS (RECIST 1.1). Following an amendment, an interim analysis of Part A was performed to assess afatinib monotherapy. Results: Patient enrolment into Part A was from April 2010 to May 2011. Of 1154 afatinib-treated patients, 91 (8%) had squamous histology; 18/91 and 40/91 had CR/PR and SD on prior E/G, respectively (by investigator). Median age was 63 yrs, 71% were male, 76% were current/ex-smokers. Median PFS on afatinib was 3.7 mths in the squamous histology subset. Of 91 patients, 42 had PFS ≥3 mths; 13 had PFS of ≥6 mths. In evaluable patients (n=77), 1 CR and 3 PRs were confirmed; 51 and 22 patients had best overall response of SD and PD, respectively. Of the 31 patients with PD on prior E/G with no intervening chemotherapy, 10 achieved confirmed disease control (2 PR; 8 SD) on afatinib. Most commonly reported grade 3/4 adverse events (AEs) in Part A were diarrhea (13%) and rash/acne (12%). The safety profile in the squamous histology subset was similar to that observed for the whole trial. Conclusions: Afatinib monotherapy demonstrated encouraging activity in treatment-refractory NSCLC patients with squamous histology that merits further evaluation.

Brigatinib (BRG) in patients (pts) with crizotinib (CRZ)-refractory ALK+ non-small cell lung cancer (NSCLC) and brain metastases in the pivotal randomized phase 2 ALTA trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20502-e20502 ◽  
Author(s):  
Sai-Hong Ignatius Ou ◽  
Marcello Tiseo ◽  
D. Ross Camidge ◽  
Myung-Ju Ahn ◽  
Rudolf M. Huber ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Review Committee ◽  
Small Cell Lung ◽  
Best Response ◽  
Independent Review ◽  
Grade 3 ◽  
A Site ◽  
To Receive ◽  
Clinical Trial Information

e20502 Background: The CNS is often a site of first disease progression in CRZ-treated ALK+ NSCLC. The ALTA trial is assessing BRG, an investigational next-generation ALK inhibitor, in pts with CRZ-refractory advanced ALK+ NSCLC, including pts with baseline brain metastases. Methods: In ALTA (NCT02094573), pts were stratified by presence of baseline brain metastases and best response to prior CRZ and randomized 1:1 to receive BRG at 90 mg qd (arm A) or 180 mg qd with a 7-d lead-in at 90 mg (arm B). Here, we show data for pts with baseline brain metastases. An independent review committee (IRC) assessed intracranial efficacy. Results: Of 222 pts (112 in arm A; 110 in arm B), 80 (71%)/74 (67%) in A/B had baseline brain metastases per investigators, with median age 49/55 y; 74%/76% had received chemotherapy. As of May 31, 2016, 51%/59% of these pts continued to receive BRG in A/B; median follow-up was 9.6/11.4 mo. Intracranial efficacy is shown in the table. Among these pts, most common treatment-emergent adverse events were: nausea 35%/46% (A/B), headache 30%/31%, vomiting 29%/31%, diarrhea 21%/38%, cough 25%/32%; grade ≥3: increased blood CPK 1%/12%, hypertension 4%/7%, increased lipase 4%/3%. Conclusions: BRG yielded substantial intracranial responses with robust iPFS and acceptable safety in ALK+ NSCLC pts with baseline brain metastases in ALTA. 180 mg (with lead-in) showed consistently improved intracranial efficacy compared with 90 mg. Clinical trial information: NCT02094573. [Table: see text]

scholarly journals Phase 2 study of ruxolitinib in combination with 5-azacitidine in patients with myelofibrosis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7063-7063 ◽  
Author(s):  
Lucia Masarova ◽  
Jorge E. Cortes ◽  
Naveen Pemmaraju ◽  
Elias Jabbour ◽  
Prithviraj Bose ◽  
...  
Keyword(s):  
Response Rate ◽  
Objective Response ◽  
Bone Marrow Fibrosis ◽  
Therapy Discontinuation ◽  
Previous Therapy ◽  
Phase 2 Study ◽  
Previously Treated ◽  
Grade 3 ◽  
Clinical Trial Information

7063 Background: Ruxolitinib (RUX) is effective in controlling symptoms and organomegaly in patients with myelofibrosis (MF). Combination with azacitidine (AZA) may further improve its efficacy. Methods: RUX 15 or 20 mg orally twice daily was given continuously since cycle 1. AZA 25 to 75 mg/m2 on days 1-5 of each 28-day cycle was added starting cycle 4. Responses were assessed per International Working Group for Myelofibrosis Research and Treatment 2013 criteria (IWG-MRT). Results: Among 44 pts enrolled between 03/2013 and 06/2016, 39 patients (89%) were evaluable for response. After median (med) follow-up of 20.4+ months (range, 0.5-37+); 24 pts (54%) are on study with a med overall survival of 39+ months. Med age was 66 years (range, 48-87), 36 pts (82%) had int-2/high IPSS score, 29 (66%) had spleen ≥5cm, and 24 (55%) were JAK2 V617F positive. Twenty five pts (57%) were previously treated. Twenty eight (72%) pts had objective response regardless of previous therapy (Table). Med time to response was 1.0 months. 7 (25%) responses occurred after the addition of AZA with med time to response of 4.2 months. In total, 23 pts (79%) had palpable spleen reduction by > 50%, which occurred after AZA was added in 6 (28%) of them. JAK2V617Fallele reduction was noted in 13 (87%) evaluable pts, including > 50% reduction in 3 pts (13%). A reduction in bone marrow fibrosis grade was observed in 12 (31%) responders, including ≥2 and 1 grade reduction in 2 and 9 pts, respectively. Grade 3/4 non-hematological and hematological toxicities occurred in 4 and 16 pts, respectively. The most common reasons for therapy discontinuation (n=17) were stem cell transplantation (n=6), lack of response (n=3) and progression to AML (n=2). Conclusions: Concomitant RUX with AZA was feasible with overall IWG-MRT response rate of 72%, including >50% spleen reduction in 79% of patients, which compares favorably to single RUX. Clinical trial information: NCT01787487. [Table: see text]

A Phase I Study of GA101 (RO5072759) Monotherapy Followed by Maintenance in Patients with Multiply Relapsed/Refractory CD20+ Malignant Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 934-934 ◽  
Author(s):  
Laurie H. Sehn ◽  
Sarit E. Assouline ◽  
Douglas A. Stewart ◽  
Joy Mangel ◽  
Pavel Pisa ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Phase I ◽  
Phase I Study ◽  
Maintenance Treatment ◽  
Malignant Disease ◽  
Response Rate ◽  
Type Ii ◽  
Grade 3 ◽  
Anti Cd20 ◽  
To Receive

Abstract Abstract 934 Background: GA101 (RO5072759) is the first humanized glycoengineered type II anti-CD20 monoclonal antibody to enter clinical trials. Preclinical studies have shown superior efficacy compared to rituximab and an initial phase I trial with 3-weekly dosing (Salles, ASH 2008) has demonstrated promising activity. The current phase I study has investigated the pharmacokinetics, safety and tolerability of escalating doses of GA101 administered on a weekly x 4 schedule followed by maintenance therapy. Methods: Patients with relapsed/refractory CD20+ malignant disease for whom no therapy of higher priority was available were treated with GA101 monotherapy administered as a flat dose on days 1, 8,15 and 22 (with first infusion administered at 50% of cohort dose). Cohort doses were escalated based on safety in a 3+3 design. Tumor response was assessed at 3 months. Patients achieving a CR or PR were eligible to receive 3-monthly maintenance GA101 × 2 years. Select patients with stable disease (SD) and major clinical benefit were also permitted to receive maintenance therapy. Results: Since January 2008, 22 patients at 5 Canadian sites have been treated with GA101 at doses ranging from 100 mg to 2000 mg. Safety data is available on all patients, 20 of whom are evaluable for response following induction. The median age was 59 yrs (47-77). Histologies included follicular lymphoma (10), CLL (5), DLBCL (3), SLL (2), MCL (1) and MZL with high-grade transformation (1). Patients were highly pretreated, receiving a median of 4 (1-7) prior therapies: 19/22 (86%) had been treated with rituximab at least once, median was twice (1-4). 11/22 patients (50%) were refractory to rituximab. GA101 was well tolerated with no dose limiting toxicities observed across the escalating dose cohorts. The most common adverse events were grade 1/2 infusion-related reactions (IRRs), characterized by fever, chills, hypo/hypertension, nausea and vomiting. IRRs were mainly associated with the first infusion (16 events), with decreased frequency in subsequent infusions (only 8 events for all subsequent infusions). There were 4 grade 3 IRRs (one associated with tumour lysis syndrome) and one grade 4 IRR (with hypoxia) on day 1, the grade 4 event leading to the only permanent discontinuation from the protocol. During the induction period, a total of 6 minor infections and one episode of febrile neutropenia were reported in 4 patients. Five cases of grade 3/4 neutropenia (1 febrile) were reported in 4 patients and 1 case of grade 3 thrombocytopenia. To date, 8 serious adverse events have been reported in 7 patients (two of which were IRRs). Two patients have died, one with DLBCL who completed induction but progressed and died prior to efficacy assessment and one with follicular lymphoma who progressed and died on day 133. Measurement of plasma cytokines during and immediately after the first infusion showed an increase in IL6 and IL8 with a smaller increase in IL10 and TNF , a pattern of change that is broadly similar to other anti-CD20 antibodies. Minimal change in complement fractions was observed, which is in keeping with the known pre-clinical profile of GA101. GA101 pharmacokinetics in this study was characterized by two clearance components, one linear and one saturable, consistent with target-mediated disposition. Peak serum concentration levels were achieved by the third dose with significant inter-patient variability in peak levels noted. The overall response rate was 25% (5 pts, all PRs) with 13 patients having SD and 2 progressing. Of those patients with SD, 6/13 had objective evidence of tumour shrinkage, with one consolidating to a PR with maintenance treatment. Clinical benefit was seen across all dosing cohorts, including rituximab-refractory patients. The overall (best) response rate in patients with lymphoma was 38% (6 PRs). In all, 8 patients have continued on to maintenance treatment following induction, 3 of whom have subsequently progressed (2 aggressive lymphoma, 1 CLL). 5 patients remain on maintenance therapy; 4 in remission with durations ranging from 73 to 258 days and one patient with SD. Conclusion: GA101 is a novel type II anti-CD20 monoclonal antibody that appears to have a safety profile similar to rituximab with promising efficacy in a clinically heterogeneous, heavily pretreated, end-stage patient population. Following review of pharmacokinetic and efficacy data, a dose of 1000 mg has been selected for ongoing phase II trials. Disclosures: Sehn: Roche, Inc: Consultancy, Honoraria, Research Funding. Stewart:Roche, Inc: Honoraria, Research Funding. Pisa:F Hoffman La Roche: Employment. Kothari:Roche Products Limited : Employment. Crump:Roche, Inc: Honoraria.

Oral Melphalan, Prednisone and Thalidomide for Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 779-779
Author(s):  
Antonio Palumbo ◽  
Sara Bringhen ◽  
Pellegrino Musto ◽  
Tommaso Caravita ◽  
Rosanna Capozzi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Response Rate ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Grade 3 ◽  
Lost To Follow Up ◽  
To Receive

Abstract In newly diagnosed multiple myeloma (MM) patients, the combination melphalan, prednisone and thalidomide (MPT) induces a fast tumor response with a high response rate, but evidence that this translate into improved outcome is limited. This multicenter trial compared the efficacy and the toxicity of oral MPT with oral melphalan and prednisone (MP) in previously untreated patients. From January 2002 to December 2004, we randomised 255 patients, who were older than 65 years of age (median age 72). Data analysis was performed on July 2005. The MPT regimen included oral melphalan (4 mg/m2 for 7 days) and prednisone (40 mg/m2 7 days) for six four week cycles plus thalidomide (100 mg per day continuously until any sign of relapse or progressive disease) The MP regimen was as MPT without thalidomide. Patients who were not assigned to receive thalidomide were permitted to cross over to receive thalidomide after relapse or disease progression. Patients treated with MPT experienced higher response rates and a longer time to progression (primary end points) than patients who did not receive thalidomide. The overall response rate was 76% for MPT and 48% for MP alone (P&lt;0.0001), and the near complete response rates were 28% and 7%, respectively (P&lt;0.0001). Median progression free survival in the MPT and in the MP groups was 33 months and 14 months, respectively (hazard ratio, 0.47; P&lt;0.001). MPT increase median progression free survival by almost 19 months. The 2-yr survival rate was 82% in MPT patients and 65% in MP patients (hazard ratio, 0.68; P=0.2). In MPT group, 33 patients did not complete the 6 courses because of progression disease (9), toxicity (16), death (2), and withdrawal of consent or lost to follow-up (6). In MP group, 32 patients did not complete the 6 courses because of progression disease (19), toxicity (3), death (3), and withdrawal of consent or lost to follow-up (7). By looking at those patients who completed the assigned 6 cycles in both arms, the 2-yr survival rate was 90% in MPT patients and 71% in MP patients, the difference was statistically significant (hazard ratio, 0.39; P&lt;0.01). Grade 3 or 4 adverse events were reported in 49% of patients treated with MPT and in 25% of those treated with MP: they included thromboembolism (12% versus 2% of patients), infections (10% versus 1%), peripheral neuropathy (10% versus 1%), and hematologic toxicity (22% versus 25%) respectively. In the first 64 patients who received MPT, grade 3–4 adverse events were reported in 58% of patients. In the last 65 MPT patients, the incidence of grade 3–4 adverse events was 40%. By comparing the first cohort with the second one, thromboembolism dropped from 22% to 3% (P&lt;0.01) and neurotoxicity from 13% to 8% (P=NS), respectively. The oral MPT was superior to the standard MP in patients with newly diagnosed myeloma. The adequate mangement of side effects reduced toxicity.

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