R2W: Subcutaneous Bortezomib, Cyclophosphamide and Rituximab (BCR) Versus Fludarabine, Cyclophosphamide and Rituximab (FCR) for Initial Therapy of WaldenstrőM's Macroglobulinemia: A Randomised Phase II Study

Abstract Introduction Earlier studies have indicated that the combination of bortezomib and rituximab is highly active in Waldenstrőm's macroglobulinemia (WM). However, there is scope to improve the complete response rate, duration of response and toxicity profile. We evaluated the efficacy and tolerability of the addition of cyclophosphamide to bortezomib and rituximab in previously untreated patients with WM. Methods Symptomatic treatment-naïve patients were enrolled into this prospective randomised (2:1), multicentre, non-comparative Phase II study (NCT01592981). Patients were stratified according to the International Prognostic Scoring System for WM. Patients were treated with BCR (Bortezomib 1.6 mg/m2 s.c. days 1, 8, 15; Cyclophosphamide 250 mg/m2 oral days 1, 8, 15; Rituximab 375mg/m2 i.v. days 1, 8, 15, 22 cycles 2 and 5 only) or FCR (Fludarabine 40mg/m2 oral days 1-3; Cyclophosphamide 250 mg/m2 oral days 1-3; Rituximab 375mg/m2i.v. days 1, 8, 15, 22 cycles 2 and 5 only) for 6 cycles repeated every 28 days. Rituximab and bortezomib were provided free of charge by Roche and Janssen, respectively. The primary endpoint was investigator assessed overall response rate (ORR) using consensus criteria. Results Sixty patients were enrolled into this study and 59 received trial treatment (BCR=42, FCR=17). Of all registered patients, 73% were male, median (range) age was 67 years (43-87), Haemoglobin 9.8 g/dL (6.5-14.0), serum IgM paraprotein 34 g/L (3.2-80.2), plasma viscosity 3.6 mPa.s (2.0-9.3) and 25/30/45% were low/intermediate/high risk respectively. Six cycles were completed by 92.9% of BCR and 76.5% of FCR patients, one patient withdrew from the study prior to starting trial treatment. Dose reductions were needed in 38.1% of BCR and 52.9% of FCR patients and treatment delays occurred in 64.3% of BCR and 64.7% of FCR patients. ORR was 97.6% in BCR patients with 78.6% achieving a major response (CR=1, VGPR=8, PR=24, MR=7, SD=1), one patient was not assessed as no evidence of WM was found upon central review; 82.4% in FCR patients with a major response rate of 76.5% (CR=0, VGPR=3, PR=10, MR=1, SD=2), one patient stopped treatment after cycle 1 due to continuing cytopenia (grade 4). Responses were also evaluated in both marrow and peripheral blood using a disease specific multiparamater flow cytometric assay. After a median follow-up of 18 months, 54 patients were progression-free; 3 patients progressed (all BCR) and 3 patients died, 2 from myelodysplastic syndrome (MDS) (both FCR) and 1 from pneumonia (BCR). Grade 3 or higher toxicities included anemia (5 [11.9%] BCR; 3 [17.6%] FCR), neutropenia (11 [26.2%] BCR; 12 [70.6%] FCR), thrombocytopenia (7 [16.7%] BCR; 6 [35.3%] FCR) and infection (2 [4.8%] BCR; 5 [29.4%] FCR). No grade 3 or higher neuropathy was reported. Conclusions BCR and FCR are both highly effective treatments for primary therapy of WM but FCR is associated with increased toxicity and concerning incidence of secondary MDS. BCR warrants further investigation in a randomised Phase III trial. Continued follow-up of R2W patients is also important to provide reliable estimates for duration of response, progression-free survival and overall survival. Disclosures Auer: Janssen: Consultancy, Other: Drug provided for clinical trial; Bristol Myers Squibb: Consultancy. Owen:Janssen: Consultancy; Roche: Honoraria; Pharmacyclics: Consultancy.

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The VcR-CVAD Regimen Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma (MCL): First Analysis of E1405 – A Phase II Study of VcR-CVAD with Maintenance Rituximab for MCL.

Blood ◽

10.1182/blood.v114.22.1661.1661 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1661-1661 ◽

Cited By ~ 6

Author(s):

Brad S Kahl ◽

Hailun Li ◽

Mitchell R Smith ◽

Randy D. Gascoyne ◽

Elisabeth Paietta ◽

...

Keyword(s):

Phase Ii ◽

Research Funding ◽

Response Rate ◽

Complete Response Rate ◽

Phase Ii Study ◽

Cell Lymphoma ◽

Complete Response ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 1661 Poster Board I-687 Introduction One approach to improving outcomes in Mantle Cell Lymphoma (MCL) is to incorporate newer targeted agents into standard chemotherapy regimens. As the proteasome inhibitor bortezomib (Velcade‘) achieved a 33% response rate in relapsed MCL, we hypothesized that the incorporation of Velcade (Vc) into a modified R-hyperCVAD chemotherapy backbone would result in a high complete response rate (CR). The new regimen, VcR-CVAD, was tested for safety and efficacy in a phase II study within the Wisconsin Oncology Network (UW) and demonstrated a CR rate of 77% (Kahl, ASH 2008). To determine the safety and efficacy of this regimen in a cooperative group setting, we initiated E1405: a phase II study of VcR-CVAD with maintenance rituximab (MR) for untreated MCL. Methods Eligible patients had histologically confirmed, previously untreated MCL, PS 0-2, and adequate end organ function. The treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1-3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1-2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1-4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients had an option to receive high dose chemotherapy and autologous stem cell transplantation (off protocol) rather than MR. The primary endpoint of the trial was the CR rate, incorporating PET imaging, to VcR-CVAD induction therapy. Results Seventy-six eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40-76), 59M:17F, 91% stage III/IV, and 39% with elevated LDH. Sixty-four patients (84%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), patient preference (2), and other/unknown (5). Response information is available on 74 patients while data is outstanding on 2 patients. The ORR was 96% (73/76; 95% CI, 89%-99%), CR rate 75% (57/76; 95% CI, 64%-84%) and the PR rate 21% (16/76; 95% CI, 13%-32%). Six of the PR patients were coded as such because of protocol violations in which a post-treatment bone marrow biopsy or PET scan was not obtained. The CR rate in the 68 completely restaged patients was 84%. Forty-four patients proceeded to planned MR while 21 patients went off protocol to SCT consolidation. Median follow up is currently too short (9 months) to assess PFS and OS. The major toxicity of the treatment regimen was expected myelosuppression. Grade 3-4 non hematologic toxicities were rare. No patients developed grade 3-4 neuropathy. There were no treatment related deaths. Conclusion The VcR-CVAD induction produced high overall response (96%) and CR rate (75%) in a representative MCL patient population treated on a cooperative group protocol. The CR rate was high and comparable to the UW pilot study (77%). No episodes of severe painful peripheral neuropathy were reported using the reduced vincristine dosage and the overall toxicity profile was very acceptable. Longer follow up is needed to determine if the high CR rate will translate into improved PFS and OS. Disclosures Kahl: Genentech: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Off Label Use: Bortezomib as front line treatment in MCL. Smith:Genentech: Research Funding; Millennium: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding. Horning:Genentech: Honoraria, Research Funding.

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Bendamustine, Bortezomib and Dexamethasone (BVD) in Patients with Relapsed-Refractory Multiple Myeloma (MM): Updated Results of a Multicenter Phase II Study

Blood ◽

10.1182/blood.v124.21.4734.4734 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4734-4734

Author(s):

Massimo Offidani ◽

Laura Maracci ◽

Laura Corvatta ◽

Liberati Anna Marina ◽

Stelvio Ballanti ◽

...

Keyword(s):

Adverse Events ◽

Phase Ii ◽

Response Rate ◽

Phase Ii Study ◽

Prior Treatment ◽

New Drugs ◽

Induction Phase ◽

Grade 3 ◽

Therapy Reduction

Abstract Introduction: Bendamustine, a bifunctional alkylating agent, exerts a mechanism of action different from that of other conventional alkylators despite it remains mostly unknown. In patients with newly diagnosed or relapsed-refractory MM bendamustine has proven to be active either as monotherapy or in combination with new drugs, particularly bortezomib and immunomodulatory agents. Methods: The preliminary results of this prospective, phase II study conducted in 22 Italian centres are recently published (Blood Cancer J. 2013, 3: e162). Here we present the conclusive results of the combination Bendamustine (70 mg/m2 days 1, 8), Bortezomib (1.3 mg/ m2 days 1, 4, 8, 11) and Dexamethasone (20 mg days 1-2, 4-5, 8-9, 11-12) (BVD) administered every 4 weeks in patients with relapsed-refractory MM of any age, with adequate cardiac, liver and hematological function, not refractory to bortezomib and treated with no more than four previous lines of therapy. The primary endpoint of this study was achievement of a response at least PR, as to IMWG criteria, after four cycles of BVD. Patients achieving a response less than a PR were taken off-study. Patients obtaining at least a PR received two additional treatment cycles followed by a 12-months consolidation phase with cycles repeated every 2 months. Therefore, patients with a PR after the induction phase could receive up to 18 months of treatment and up to 12 cycles of BVD. Results: 75 patients were included in the study. Median age was 68 years (range 41-85 years), 26.5% had ISS stage 3, 19% IgA myeloma and 9% renal failure. Eight of 36 evaluable patients (22%) had high-risk cytogenetics. Patients had received a median of one prior line of therapy (range 1-4). All patients had received prior treatment with new drugs, such as thalidomide (57%), lenalidomide (54.5%), bortezomib (46.5%) or both (20%). Twenty-four patients (32%) were refractory to IMIDs. Best response rate was 75%, including 14 CRs (20%), 22 VGPRs (24%) and 27 PRs (31%). Five patients (6.5%) died early. Only prior treatment with bortezomib significantly reduced the response rate ≥ PR (48.5% vs 80%; P = 0.004). At a median follow-up of 27 months (range 18-38), 45 patients had progressed and 43 had died. Median TTP and PFS were 17 and 12.5 months, respectively while median OS was 24 months (40% at 3 years). After longer follow-up, prior therapy with bortezomib plus lenalidomide was confirmed as the only factor that significantly reduced TTP (9 vs 19 months; HR = 2.7; 95% CI = 1.3-5.8; P = 0.009), PFS (9 vs 15 months; HR = 2.1; 95% CI = 1.2-3.8; P = 0.020) and OS (17 vs 32 months; HR = 2.1; 95% CI = 1.2-3.9; P = 0.043). Grade 3-4 adverse events occurred in 55% of patients leading to therapy reduction in 24% and to protocol discontinuation in 11% of patients. The most frequent severe adverse events were thrombocytopenia (28%), neutropenia (20%), infections (12%), peripheral neuropathy (9%), gastrointestinal (5%) and cardiovascular events (4%). Compared with younger, patients aged > 70 years had a significantly higher incidence of grade 3-4 side effects particularly thrombocytopenia and infections with, consequently, a higher rate of therapy reduction and discontinuation. Moreover, 4/5 early deaths occurred in patients aged more than 70 years. Conclusions: BVD combination is an effective and well tolerated regimen in relapsed-refractory MM. Data suggest that the optimal target of BVD maybe patients younger than 70 years who has not previously received both bortezomib and lenalidomide. Disclosures Offidani: Mundipharma, Janssen: Honoraria. Off Label Use: Bendamustine. Corvatta:Janssen: Honoraria. Ballanti:Janssen: Honoraria. Brunori:Janssen: Honoraria.

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Results of a Phase II Multicenter Study of Immunochemotherapy with Fludarabine, Cyclophosphamide and Rituximab (FCR) for Symptomatic Waldenstrom’s Macroglobulinemia

Blood ◽

10.1182/blood.v112.11.3692.3692 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3692-3692

Author(s):

Alessandra Tedeschi ◽

Giulia Benevolo ◽

Marzia Varettoni ◽

Marta Battista ◽

Sara Miqueleiz ◽

...

Keyword(s):

Phase Ii ◽

Severe Neutropenia ◽

Waldenström’S Macroglobulinemia ◽

The Third ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Grade 3 ◽

Waldenström's Macroglobulinemia

Abstract Background: In Waldenstrom’s Macroglobulinemia (WM) the combination of Fludarabine (F) + Cyclophosphamide (C) induces response rates of 85% and 55–89% in previously untreated and relapsed/refractory pts, respectively. Rituximab (R) monotherapy is active and well tolerated in WM and there is evidence that R in association with chemotherapy may improve the quality of responses. Few studies with a small number of pts demonstrated the feasibility of FCR regimen in WM with responses ranging from 79% to 90%. Methods: in February 2005 we started a multicenter, two-stage design, phase II study on the effectiveness, tolerability and safety of FCR in symptomatic WM pts previously untreated or relapsed/refractory to one line of chemotherapy. Pts previously treated with FC combination or monoclonal antibodies were excluded. Treatment consisted of: R 375 mg/sqm d1, F 25 mg/sqm and C 250 mg/sqm iv d 2–4 every 4 weeks. Accrual of the planned 43 pts ended on March 2008. The first assessment of the disease, including bone marrow (BM) evaluation, was performed after the third FCR course. Pts with progressive disease (PD) were considered as failure, responding pts or those with SD went on to receive up to 3 further courses. Results: 18 females and 25 males, median age 65 yrs, were enrolled. Median time from diagnosis to FCR was 25.5 mos; 65% of pts were in first line treatment, 7% and 28% in relapsed and refractory disease, respectively. According to the International Scoring System for WM (ISSWM) 39.5% of pts were low risk, 51.2% intermediate and 9.3% high risk. As of August 10, 2008 analysis has been performed on 40 pts; final evaluation will be available in October 2008, since 3 pts completed treatment but response data are pending. A median of 6 courses (range 2–6) have been administered; 65% of pts received the planned 6 cycles. Reasons for not completing the 6 courses were: 1 PD, 1 hemolytic anemia, 1 hypersensitivity reaction to R, 8 severe neutropenia, 3 pneumonia. Thirty-six pts (90%) received ≥ 4 courses of therapy and have been considered valuable for response. As the protocol was designed before 2006, response criteria did not include MR and were categorized as follows: 14% CR, 69% PR, 14% SD, 3% PD (according to the updated criteria: 14% CR, 69% PR, 6% MR, 8% SD, 3% PD). Nine of the 25 patients in PR could be considered as in “near CR” as they fulfilled criteria for CR except for the persistence of a positive immunofixation. None of the patient and disease variables (age, sex, light chain, disease status, Hb, PLT and Ig level, % BM infiltration, b2m, albumin, creatinine, ISSWM) was significant for the achievement of a response. A comparison was performed between responses achieved after the third course and after the end of treatment. We observed that there was a significant improvement of responses (p=0.015) at last response assessment (5 CR+ 25 PR+ 5 SD+ 1 PD vs 2 CR+ 20 PR + 13 SD + 1 non evaluated after the third FCR course). Extrahematological toxicity was manageable and mostly limited to grade 1 and 2. An episode of grade 3 asthenia was reported. Twenty-one pts developed Rituximab-related reactions, grade 2 maximum, limited to the first or second infusion. In one case FCR treatment was interrupted because of grade 3 cutaneous hypersensitivity. Neutropenia occurring in 60% of courses was the main haematological toxicity, which caused the interruption of planned treatment in 20% of pts. Thirty-five percent of pts developed long lasting episodes of neutropenia (median duration 5 mos, range 3–15) mostly after 6 FCR courses (range 3–6). None of the clinical and disease characteristics analysed were statistically predictive of neutropenia development. Three episodes of pneumonia and 2 of FUO requiring hospitalization were observed during neutropenia. During follow-up we observed a late improvement of responses, as 3 further PR converted to CR (after a median of 10 mos), and 1 SD to PR (after 10 mos). Median DFS and OS have not been reached after a median follow-up of 15.1 and 20.4 mos, respectively. Conclusion: FCR produced a high ORR with good quality of responses, which improved over time. We registered, however, high incidence of neutropenia with long lasting neutropenic episodes limiting the administration of the planned therapeutic program. According to the analysis of our population it seems reasonable to reduce to four the number of planned FCR courses, administering, if required, Rituximab as consolidation/maintenance to avoid myelotoxicity.

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Bendamustine Is Highly Effective for Relapsed or Refractory Indolent B-Cell Non-Hodgkin Lymphoma (B-NHL) and Mantle Cell Lymphoma (MCL): Final Results of a Japanese Multicenter Phase II Study.

Blood ◽

10.1182/blood.v114.22.3694.3694 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3694-3694 ◽

Cited By ~ 3

Author(s):

Michinori Ogura ◽

Toshiki Uchida ◽

Kiyoshi Ando ◽

Ken Ohmachi ◽

Kuniaki Itoh ◽

...

Keyword(s):

Phase Ii ◽

Response Rate ◽

Phase Ii Study ◽

Complete Response ◽

Hematologic Toxicity ◽

Multicenter Phase ◽

Number Of Patients ◽

Highly Effective ◽

Grade 3

Abstract Abstract 3694 Poster Board III-630 [Background and Purpose] Bendamustine hydrochloride is a bifunctional alkylating agent with novel mechanisms of action. Although bendamustine is known to have anti-tumor activity against indolent B-NHL as a single agent, efficacy in MCL with bendamustine monotherapy has not been reported. To assess the efficacy and toxicity of bendamustine in patients with relapsed indolent B-NHL and MCL, we conducted a multicenter phase II study. [Patients and Methods] Patients diagnosed with relapsed or refractory indolent B-NHL or MCL, 75= or >age= or >20, and PS 0-1 (ECOG) were enrolled in the study. Bendamustine was administered intravenously at a dose of 120 mg/m2 infused over 60 minutes on days 1 and 2 of each 21-day treatment cycle for up to 6 cycles (minimum of 3 cycles). The primary endpoint was the overall response rate (ORR). Tumor response was assessed by a central radiological review committee according to the International Workshop Criteria for NHL (1999). [Results] A total of 69 patients were enrolled and treated, including 52 (75%) cases of follicular lymphoma (FL) and 11 (16%) cases of MCL, ages 33 to 75 years, with predominantly stage III/IV indolent B-NHL (86%) or MCL (64%). The median number of unique prior therapies was two (range, 1 to 16), and sixty-six patients (96%) had received rituximab as a prior therapy. Twenty-nine patients (42%) completed the planned six cycles of chemotherapy, with fifty patients (72%) receiving 3 or more cycles. Dose reduction of bendamustine was required in 11 patients (16%). The ORR was 91% (63 of 69 patients; 95% CI, 82% to 97%) with a complete response (CR) rate of 67% (%CR), including %CRu (46 of 69 patients; 95% CI, 54% to 78%). The ORR in FL and MCL was 90% and 100%, respectively. The %CR in FL and MCL was 66% and 73%, respectively. Median progression-free survival (PFS) for all 69 patients was not reached at the median follow-up duration of 248 days (39-359 days). Median PFS for indolent B-NHL (58) and MCL (11) patients was not reached at the median follow-up duration of 254 days and 226 days, respectively. Hematologic toxicities, including grade 4 lymphopenia (72%) and neutropenia (48%), were the most frequently reported toxicities in patients. Non-hematologic toxicities were mild, with no grade 4 non-hematologic toxicity recorded. The most frequently reported grade 3 non-hematologic toxicities were GI toxicities (9%) including grade 3 vomiting (4%) and anorexia (3%), and infections (7%) which included one case of grade 3 febrile neutropenia, pneumonia, herpes infection, and viral pharyngitis. [Conclusion] Bendamustine monotherapy is a highly effective and less toxic treatment in patients with relapsed or refractory indolent B-NHL and MCL who have been pretreated (96%) with rituximab. It is noteworthy that a very high complete response rate (73%) was achieved in relapsed or refractory MCL patients although the number of patients was relatively small. Disclosures: No relevant conflicts of interest to declare.

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Efficacy and Safety of Orelabrutinib in Relapsed/Refractory Waldenstrom's Macroglobulinemia Patients

Blood ◽

10.1182/blood-2021-149350 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 46-46

Author(s):

Daobin Zhou ◽

Jie Jin ◽

Zheng-zheng Fu ◽

Shuhua Yi ◽

Wei Li Zhao ◽

...

Keyword(s):

Bone Marrow ◽

Adverse Events ◽

B Cell ◽

Response Rate ◽

Safety Data ◽

Efficacy And Safety ◽

Major Response ◽

Grade 3 ◽

Waldenström's Macroglobulinemia

Abstract Background Waldenstrom's Macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with immunoglobulin M (IgM) monoclonal gammopathy. Bruton's tyrosine kinase (BTK) plays a key role in signaling pathways for the survival of WM clone, particular in patients harboring MYD88 L265P mutations. However, due to target selectivity issue, Clinical uses of early BTK inhibitors are still compromised with off-target activities to many other kinases besides BTK. Orelabrutinib is a novel, highly potent small molecule inhibitor of BTK with superior selectivity for B-cell malignancies and autoimmune diseases. Preliminary efficacy and safety data of ICP-CL-00105 in relapsed/refractory WM patients are presented here. Methods ICP-CL-00105 is a single arm, multiple centers, open label, phase 2 study in clinical and histopathological confirmed patients with R/R WM requiring treatment per IWWM-7. MYD88 and CXCR4 mutations were assessed in bone marrow samples at baseline. Orelabrutinib at a daily dose of 150mg was administered orally until disease progression or unacceptable toxicity. Blood samples for IgM were assessed at baseline and every cycle for 6 cycles and every 3 cycles thereafter by central lab. Responses were assessed in accordance with IWWM-6 and NCCN guidelines. The primary endpoint was major response rate (MRR) as assessed by IRC. Key secondary endpoints were MRR as assessed by investigator, overall response rate (ORR), duration of major response (DOMR), progression-free survival (PFS), OS, changes in IgM levels from baseline, improvement on hemoglobin levels and safety. Treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs) were assessed according to NCI CTCAE v4.03. Results As of June 1, 2021, for the 47 patients the median follow-up duration was 10.5 months. The median age was 63 years (range, 56-68 years), 40 patients (85.1%) were male. 87.2% of patients were at intermediate or high risk according to the Prognostic Scores (IPSS). The proportion of patients with MYD88 L265PCXCR4 wildtype was 83% at baseline. With a median duration of treatment of 9.2 months, MRR was 74.5% as assessed by investigator. ORR was 87.2% with 97.9% patients achieved disease control. The estimated 12-month DOMR were 89.5%. The estimated 12-month PFS and OS were 88.0% and 92.3%, respectively. The median PFS and median OS have not been reached. The MRR was higher in patients with MYD88 L265PCXCR4 wildtype (79.5%). The median IgM level was 30.3g/L at baseline. The decline in the serum IgM levels from baseline were observed with a median reduction by 79.0% (IQR: -89.4, -57.2). The median hemoglobin level at baseline was 102g/L. Durable improvement in hemoglobin levels was found in 83% of patients with a median maximal improvement of 40g/L (IQR: 24.0, 62.0). Safety data were summarized by the cutoff date of June 1, 2021. The most commonly reported AEs were thrombocytopenia (27.7%)，neutropenia (14.9%), leukopenia (10.6%), upper respiratory infection (14.9%)，weight increased (14.9%), influenza-like disease (12.8%) and rash (10.6%). Most reported AEs (89.5%) were grade 1-2. 16 patients (34.0%) reported grade ≥ 3 TEAE while 9 patients (19.1%) reported grade ≥ 3 TRAE. There was no reported grade ≥3 atrial fibrillation and/or atrial flutter, or grade ≥3 diarrhea. Only One TRAE (2.1%) resulted in drug discontinuation. Conclusion Orelabrutinib has demonstrated substantial efficacy in treating r/r WM patients under short-term follow-up. It has shown favorable safety and tolerability profile with limited off-target adverse effects. It has the potential to be a promising treatment option for r/r WM patients. Disclosures Hu: Astellas Pharma, Inc.: Research Funding. Tian: Innocare pharma: Current Employment. Zhu: Innocare pharma: Current Employment. Zhang: Innocare pharma: Current Employment. Zhao: Innocare pharma: Current Employment. Zhang: Innocare pharma: Current Employment.

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Neoadjuvant combined modality therapy with weekly docetaxel (D) and cisplatin (P), 5-fluorouracil (5FU) continuous infusion (c.i.) and concurrent radiotherapy (RT) provides high pathological response rate in esophageal cancers (EC): A phase II study

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.4057 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 4057-4057 ◽

Cited By ~ 1

Author(s):

F. Pasini ◽

G. De Manzoni ◽

A. Grandinetti ◽

C. Pedrazzani ◽

C. Griso ◽

...

Keyword(s):

Phase Ii ◽

Response Rate ◽

Phase Ii Study ◽

Combined Modality Therapy ◽

Complete Response ◽

Pathological Response ◽

Hematological Toxicity ◽

Weekly Schedule ◽

Grade 3

4057 Background: The achievement of pathological complete response (pCR) is deemed essential to improve survival in EC. In a phase I study (Pasini et al, Ann Oncol 16; 1123, 2005) we demonstrated the feasibility of a novel protocol of neoadjuvant chemoradiation based on weekly D and P, c.i. of 5-FU and concurrent RT. Based on the promising results of the study, we then performed a phase II study aimed at evaluating pathological response rate and toxicity. Methods: 50 pts with stage II-III EC (26 adenocarcinomas) were enrolled (Simon test: P0=0.2, P1=0.6, alpha 0.05 beta 0.1; 54 pts); median age was 59 yrs (42–73). Treatment consisted of D 35 mg/m2 and P 25 mg/m2 d 1,8,15,29,36,43,50,57 plus 5-FU 180 mg/m2 c.i. d 1–21 and 150 mg/m2 c.i. d 29–64; concurrent RT (50 Gy) started on d 29. Surgery was performed 6 to 8 weeks after completion of RT. Results: 49/50 pts (98%) completed the planned chemo-radiation. Median follow-up is 22 mo (7–39). During chemo-radiation, grade 3–4 hematological toxicity occurred in 9 pts (18%)(4 pts grade 4) requiring GCSF support and postponement of CT of one week in 4. One HCV+ pt discontinued CT and continued with RT alone. In the last 2 weeks 12 pts (24%) experienced grade 3 non-hematological toxicities (asthenia, esophagitis, nausea) without need of treatment discontinuation. There was a fatal pulmonary embolism in a non neutropenic pt after completion of the therapy. 45 pts underwent surgery, while 5 did not (2 refusal). Pathological findings: pT0 pN0 (pCR): 25 (50%); pTrm pN0: 6 (12%)[residual microfoci]; pT2 pN0: 1 (2%); pT0–4 pN+: 9 (18% ); R+:4 ( 8%). Response rate was similar between adeno and squamous cell carcinoma. With a median follow-up of 24 mo, only 2 of 25 pCRs (8%) died (1 relapse, 1 postoperative death). Conclusions: i) a substantial pCR rate (50%) was achieved; ii) the weekly schedule allowed concomitant chemo-radiation at cumulative doses otherwise impossible with standard three weeks protocols; iii) because of the acceptable, but not negligible toxicity, this protocol requires to be managed in dedicated institutions. No significant financial relationships to disclose.

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Phase II study of docetaxel and cisplatin in advanced non-small-cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.5.1948 ◽

1998 ◽

Vol 16 (5) ◽

pp. 1948-1953 ◽

Cited By ~ 60

Author(s):

J Zalcberg ◽

M Millward ◽

J Bishop ◽

M McKeage ◽

A Zimet ◽

...

Keyword(s):

Lung Cancer ◽

Phase Ii ◽

Advanced Nsclc ◽

Response Rate ◽

Phase Ii Study ◽

Performance Status ◽

Objective Response ◽

Small Cell ◽

Small Cell Lung ◽

Grade 3

PURPOSE Docetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, France) and cisplatin are two of the most active single agents used in the treatment of non-small-cell lung cancer (NSCLC). A recently reported phase I study of the combination of docetaxel and cisplatin recommended a dose of 75 mg/m2 of both drugs every 3 weeks for subsequent phase II study. PATIENTS AND METHODS Eligible patients were aged 18 to 75 years with a World Health Organization (WHO) performance status < or = 2 and life expectancy > or = 12 weeks, with metastatic and/or locally advanced NSCLC proven histologically or cytologically. Patients were not permitted to have received prior chemotherapy, extensive radiotherapy, or any radiotherapy to the target lesion and must have had measurable disease. Concurrent treatment with colony-stimulating factors (CSFs) or prophylactic antibiotics was not permitted. Docetaxel (75 mg/m2) in 250 mL 5% dextrose was given intravenously (i.v.) over 1 hour immediately before cisplatin (75 mg/m2) in 500 mL normal saline given i.v. over 1 hour in 3-week cycles. Premedication included ondansetron, dexamethasone, promethazine, and standard hyperhydration with magnesium supplementation. RESULTS A total of 47 patients, two thirds of whom had metastatic disease, were entered onto this phase II study. The majority of patients were male (72%) and of good (WHO 0 to 1) performance status (85%). All 47 patients were assessable for toxicity and 36 were for response. Three patients were ineligible and eight (17%) discontinued treatment because of significant toxicity. In assessable patients, the overall objective response rate was 38.9% (95% confidence limits [CL], 23.1% to 56.5%), 36.1% had stable disease, and 25% progressive disease. On an intention-to-treat analysis, the objective response rate was 29.8%. Median survival was 9.6 months and estimated 1-year survival was 33%. Significant (grade 3/4) toxicities included nausea (26%), hypotension (15%), diarrhea (13%), and dyspnea mainly related to chest infection (13%). One patient experienced National Cancer Institute (NCI) grade 3 neurosensory toxicity after eight cycles. Grade 3/4 neutropenia was common and occurred in 87% of patients, but thrombocytopenia > or = grade 3 was rare (one patient). Significant (grade 3/4) abnormalities of magnesium levels were common (24%). Febrile neutropenia occurred in 13% of patients and neutropenic infection in 11%, contributing to two treatment-related deaths. No neutropenic enterocolitis or severe fluid retention was reported. CONCLUSION Compared with other active regimens used in this setting, the combination of docetaxel and cisplatin in advanced NSCLC is an active regimen with a similar toxicity profile to other combination regimens.

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Pyrotinib in HER2-Mutant Advanced Lung Adenocarcinoma After Platinum-Based Chemotherapy: A Multicenter, Open-Label, Single-Arm, Phase II Study

Journal of Clinical Oncology ◽

10.1200/jco.20.00297 ◽

2020 ◽

Vol 38 (24) ◽

pp. 2753-2761 ◽

Cited By ~ 2

Author(s):

Caicun Zhou ◽

Xingya Li ◽

Qiming Wang ◽

Guanghui Gao ◽

Yiping Zhang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Phase Ii ◽

Objective Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Objective Response ◽

Unmet Need ◽

Open Label ◽

Platinum Based Chemotherapy ◽

Grade 3

PURPOSE Targeted therapies against non–small-cell lung cancer (NSCLC) harboring HER2 mutations remain an unmet need. In this study, we assessed the efficacy and safety of pyrotinib in patients with HER2-mutant advanced NSCLC in a prospective, multicenter, open-label, single-arm, phase II study. PATIENTS AND METHODS Patients with stage IIIB or IV HER2-mutant lung adenocarcinoma who were previously treated with platinum-based chemotherapy were enrolled to receive pyrotinib at a dose of 400 mg/d for 21-day cycles. The primary end point was objective response rate per independent review committee (IRC). RESULTS Between October 20, 2016, and December 10, 2018, 60 patients received pyrotinib monotherapy. At baseline, 58 (96.7%) were stage IV, and 25 (41.7%) received at least 2 lines of prior chemotherapy. As of data cutoff on June 20, 2019, IRC-assessed objective response rate was 30.0% (95% CI, 18.8% to 43.2%). All subgroups of patients with different HER2 mutation types showed a favorable objective response rate. The objective response rates were similar between patients with and without brain metastases (25.0% v 31.3%). The median duration of response was 6.9 months (95% CI, 4.9 to 11.1 months). The median progression-free survival was 6.9 months (95% CI, 5.5 to 8.3 months) per IRC. The median overall survival was 14.4 months (95% CI, 12.3 to 21.3 months). Treatment-related adverse events of grade 3 or 4 occurred in 28.3% of patients, with the most common being diarrhea (20.0%; all grade 3). No treatment-related deaths were reported. CONCLUSION Pyrotinib showed promising antitumor activity and an acceptable safety profile in chemotherapy-treated patients with HER2-mutant NSCLC.

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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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Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.8.2739 ◽

1998 ◽

Vol 16 (8) ◽

pp. 2739-2744 ◽

Cited By ~ 193

Author(s):

Y Bécouarn ◽

M Ychou ◽

M Ducreux ◽

C Borel ◽

F Bertheault-Cvitkovic ◽

...

Keyword(s):

Phase Ii ◽

Response Rate ◽

Phase Ii Trial ◽

Sensory Neuropathy ◽

Progression Free Survival ◽

Free Survival ◽

Duration Of Response ◽

Grade 3 ◽

Colorectal Cancer Patients ◽

Peripheral Sensory

PURPOSE To evaluate the objective tumor response rate and safety profile of oxaliplatin when administered to patients with previously untreated metastatic colorectal adenocarcinoma. PATIENTS AND METHODS A total of 39 patients were entered onto this phase II trial. One patient was excluded for having had a second cancer, so the study was based on 38 patients. Patients were treated with oxaliplatin 130 mg/m2 as a 2-hour infusion on day 1, every 21 days. Patients were assessed for response every three courses. All clinical and radiologic data were reviewed by an external panel of experts, with their assessment being considered definitive. RESULTS Nine partial responses (PRs) were observed (response rate, 24.3%; 95% confidence interval, 11.8% to 41.2%). The median duration of response was 216+ days. Fifteen patients (40.5%) had stable disease and 13 (35.2%) had progressive disease. The median progression-free survival time for all patients was 126+ days (range, 21 to 447+). The main toxicity was peripheral sensory neuropathy. Grade 3 neurotoxicity (National Cancer Institute common toxicity criteria [NCI-CTC]) was reported in 13%. Hematologic and gastrointestinal toxicities were mild. The incidence of grade 3 neutropenia was 5.2%, while that of grade 3 or 4 thrombopenia was 7.9%. Vomiting (grade 3 or 4) occurred in 7.9% of patients and grade 3 diarrhea in 2.6%. CONCLUSION This phase II study provides clear evidence of the safety and efficacy of oxaliplatin monotherapy at this dose and schedule in patients with previously untreated metastatic colorectal carcinoma.

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