Sequential Intravenous to Oral Proteasome Inhibitor Based Regimens for the Treatment of Newly Diagnosed Multiple Myeloma Patients: A Real-World Study

Objective To assess in-class transition (iCT) from intravenous bortezomib-based induction to all-oral ixazomib-based treatment improving proteasome inhibitor-based continuous therapy with efficiency, safety and convenience in clinical practice. Methods In this real-world retrospective study from Chinese seven hospitals during Oct, 2017-Jul, 2020, we analysed newly diagnosed multiple myeloma (NDMM) patients without transplantation, who achieved at least partial response of bortezomib-based introduction, and then received ixazomib-based regimen for 2 years or until progression/intolerant toxicity. Primary endpoint: progression-free survival (PFS). Key endpoints included response rate, therapy duration and adverse event (AE). Results 96 patients were enrolled in this study (median age 61 years; 25% ≥ 65 years; 7% ≥ 75 years; 61% male; ISS stage I/II/III 10%/35%/55%; IgG/IgA/IgD/IgE/light chain /double clonal /non-secretory 50%/18%/2%/1%/26%/1%/2%). R-ISS stage was estimated in 85 patients (stage I/II/III 6%/78%/16%). 35% high risk(HR) (27/78) and 65% standard risk (SR)(51/78) were tested by metaphase fluorescence in situ hybridization (M-FISH) according to Mayo clinic risk stratification. 96 patients received median 5 cycles (2-12) of bortezomib-based regimen including VD1/VRD1/VTD1/VCD1/PAD1/PD2D1, and median 6 cycles (1-17) of iCT regimen including ID1/IRD1/ITD1/ICD1 (30/96,43/96,10/96,13/96), three-drug ixazomib-based regimens account for the majority (66/96). Median duration of total PI therapy was 11.3 months and of ixazomib-based regimen was 5.3 months. With 13 months median follow-up, 18-month progression free survival (PFS) rate was 87% (95% confidence interval,78-95) from the start of bortezomib-based induction and 82% (95% confidence interval,70-94) from the start of ixazomib-based treatment(Figure 1A), 79% patients remain on therapy at data cutoff. After bortezomib-based induction, overall response(ORR) rate was 100% (strict complete response [sCR], 10/96, 10%; complete response [CR], 31/96, 32%; very good partial response [VGPR], 24/96, 26%; partial response [PR], 31/96, 32%) and 88% (sCR 22/96, 23%; CR, 28/96, 29%; VGPR, 16/96, 17%; PR, 18/96, 19%) at data cutoff. There were 3 PR improved to VGPR, 4 VGPR improved to CR, 1 PR, 4 VGPR and 5 CR improved to sCR (Figure 1B). ORR of HR patients were 100% and 85%(23/27), 1 PR improved to VGPR, 1PR improved to CR, 4CR improved to sCR; ORR of SR patients were 100% and 85% (45/51), 2PR improved to VGPR, 5VGPR improved to CR, 4VGPR and 3CR improved to sCR, before and after ixazomib-based regimen, respectively. Among 66 patients who transited to IRD1/ITD1/ICD1 regimen, medium duration of total PI therapy was 11.0 months and of ixazomib-based regimen was 5.4 months, 77% patients remain on therapy. ORR rate was 100% (sCR, 7/66, 11%; CR, 16/66, 24 %; VGPR, 16/66, 24%; PR, 27/66, 41%) and 91% (sCR 15/66, 23%; CR, 18/66, 27%; VGPR, 9/66, 14%; PR, 18/66, 27%) at data cutoff, 3 PR improved to VGPR, 4PR and 6 VGPR improved to CR, 4 VGPR and 3 CR improved to sCR. ORR of HR (23/52) patients were 100% and 96%, ORR of SR patients (29/52)were 100% and 86% before and after ixazomib-based regimen, respectively. The ixazomib-safety profile was consistent with previous clinical trial data. In our study, 59% (57/96) of patients had any grade adverse events AE. In which, the most frequent grade <=2 AEs were peripheral neuropathy(PN) (31%, 31/96, PN of 23 patients began after bortezomib-based induction), nausea and vomiting (33%), diarrhea (5%), constipation (4%), incomplete intestinal obstruction (3%), fatigue (2%), edema (1%), abdominal distension (1%) , anorexia (1%), rash(1%) , weakness of lower limbs (1%). The most frequent grade 3/4 AEs were agranulocytosis (2%) , rash (2%), PN (2%, occurred after bortezomib-based induction). Treatment discontinued of ixazomib-based regimen are PN (6/96), incomplete intestinal obstruction (1/96), agranulocytosis (1/96), rash (2/96). Conclusion In real-world China MM population, NDMM patients are sensitive to PI-based continuous therapy with satisfied response rate; iCT can permit prolonged PI-based therapy with promising efficacy and tolerated adverse events. Note: VD1, VRD1, VTD1, VCD1, PAD1, PD2D1, IRD1, ITD1, ICD1 : I: ixazomib, R: lenalidomide, T: thalidomide, C: cyclophosphamide, V: bortezomib, D1: dexamethasone P: bortezomib, A: adriamycin D2: liposome doxorubicin Disclosures No relevant conflicts of interest to declare.

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Combination of Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) for Relapsed Multiple Myeloma: Results of a Phase I/II Clinical Trial.

Blood ◽

10.1182/blood.v108.11.407.407 ◽

2006 ◽

Vol 108 (11) ◽

pp. 407-407 ◽

Cited By ~ 1

Author(s):

Antonio Palumbo ◽

Maria Teresa Ambrosini ◽

Giulia Benevolo ◽

Patrizia Pregno ◽

Norbert Pescosta ◽

...

Keyword(s):

Partial Response ◽

Phase I ◽

Response Rate ◽

Oral Prednisone ◽

Progression Free Survival ◽

Complete Response ◽

Second Line ◽

Open Label ◽

Free Survival ◽

Line Of Therapy

Abstract BACKGROUND: In newly diagnosed patients, the addition of thalidomide or bortezomib (Velcade™) to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter, open-label, non randomized, phase I/II trial, the safety/efficacy profile of the 4 drug combination, bortezomib (Velcade™), melphalan, prednisone, and thalidomide (VMPT) was evaluated in patients with relapsed/refractory myeloma. METHODS: Bortezomib was administered by IV bolus on days 1, 4, 15, 22 at three dose levels: in the first cohort (10 patients) at 1.0 mg/m2; in the second cohort (10 patients) at 1.3 mg/m2and in the third cohort (10 patients) at 1.6 mg/m2. Oral melphalan was administered at 6 mg/m2 on days 1–5, oral prednisone at 60 mg/m2 on days 1–5. Thalidomide was delivered at 50 mg on days 1–35. Each course was repeated every 35 days for a total of 6 courses. RESULTS: Thirty patients, median age 66 years (range 38–79), with relapsed or refractory myeloma were enrolled. Fourteen patients received VMPT as second line of therapy, 16 as third line. Twenty patients received prior autologous transplant, 10 conventional chemotherapy and 9 thalidomide-based regimens. After a median of 6 courses, 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good partial response (VGPR). Among patients who received VMPT as second line treatment, the PR rate was 79%, and the immunofixation negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 non-hematological adverse events included: infections (5 patients), fatigue (1), vasculitis (1) and peripheral neuropathy (2); no grade 4 toxicities were recorded. CONCLUSIONS: Initial results showed that VMPT is an effective salvage therapy with a high proportion of responses. Toxicities were manageable. The incidence of neurotoxicities was unexpectedly low.

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Targeting Complete Response with Upfront Bortezomib Followed By Autologous Transplantation and Consolidation Therapy for Untreated Multiple Myeloma (TUBA study)

Blood ◽

10.1182/blood.v128.22.3463.3463 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3463-3463

Author(s):

Hideki Nakasone ◽

Kiriko Terasako-Saito ◽

Teiichi Hirano ◽

Atsushi Wake ◽

Seiichi Shimizu ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Progression Free Survival ◽

Complete Response ◽

Induction Treatment ◽

High Dose ◽

Induction Phase ◽

Consolidation Therapy ◽

Newly Diagnosed ◽

Free Survival

Abstract [Background] Multiple myeloma (MM) is generally considered incurable. Recently, novel drugs, including bortezomib, have demonstrated a survival benefit for newly diagnosed MM patients compared with classical treatments. Complete response (CR) after treatment is known to be associated with superior progression-free survival. Thus, we prospectively evaluated the efficacy and safety of boretezomib + dexamethasone (BD) for patients with newly diagnosed MM, followed by autologous hematopoietic stem cell transplantation (ASCT). We added BD consolidation therapy to aim CR if CR was not achieved after ASCT. [Patients and methods] This clinical study prospectively recruited newly diagnosed MM patients eligible for ASCT between 2010 and 2012. Due to health insurance issues in Japan, two courses of high-dose dexamethasone (HD-DX) had been administrated prior to BD induction treatment until Nov. 2011, while BD was administrated as an initial induction treatment since Dec. 2011. BD induction treatment included 1.3 mg/m2 of bortezomib on days 1, 4, 8, and 11 with 20mg of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. This BD induction cycle was repeated every 3 weeks for 4 courses. Thereafter, filgrastim-based mobilization and ASCT following high-dose melphalan administration was performed. If patients did not achieve CR after ASCT, BD consolidation therapy (bortezomib: 1.3 mg/m2 on days 1, 8, and 15; dexamethasone 20 mg/day on days 1-2, 8-9, and 15-16) every 4 weeks was added to target CR (Figure 1) (UMIN-CTR: UMIN000002442). [Results] The median observational duration among survivors was 1536 days (range: 464-2023) at this analysis. Of the 47 enrolled MM patients, 46 (male 27; female 19) were eligible for BD induction treatment, while the remaining one achieved CR before BD induction. The median age of the patients was 59 (range: 35-67) years. Of the 44 patients whose karyotype analyses were available, normal karyotype was observed in 35. Abnormal karyotype included complex type in 4, diploid in 1, and other abnormalities in 4. FISH revealed deletion of p53 in 5 of 39 patients whose information was available; deletion of 13-chromosome in 16 of 42, IgH-MAF fusion in 1 of 40; IgH-FGFR3 fusion in 5 of 41; IgH-BCL1 fusion in 9 of 39. Of the 46 MM patients, 19 received HD-DX prior to BD induction, and 34 received ASCT after BD induction treatment (Figure 1). During the BD induction phase, 3 patients experienced disease progression, and BD treatment was discontinued in 9 patients because of their consent withdrawal (n=2) and adverse events (n=7) including interstitial pneumonia in 2, persistent neuropathy in 1, CMV enterocolitis in 1, heart failure in 1, diabetes mellitus in 1, and liver dysfunction in 1. After BD induction phase (n=46), their response was >= CR in 4 (8%), very good partial response (VGPR) in 10 (22%), partial response (PR) in 18 (39%), stable disease (SD) in 2 (4%), and progression or withdrawal in 12 (26%). After ASCT, their response was >=CR in 9 (20%), VGPR in 11 (24%), PR in 12 (26%), SD in 1 (2%), and additional progression or withdrawal in 1 (2%). Of the 24 patients who received ASCT and whose response was less than CR, 21 received BD consolidation therapy for a median of 4 courses (range: 1- 8). BD consolidation was discontinued in 4 patients due to persistent neuropathy or cytopenia. Finally, maximum response after ASCT with or without BD consolidation was >= CR in 19 (41%), VGPR in 7 (15%), PR in 6 (13%), < SD in 2 (2%, Figure 2). Through BD consolidation, CR was achieved in 8 of 11 patients with post-ASCT VGPR and 2 of 12 patients with post-ASCT PR. In total, 4-year progression-free survival (PFS) and overall survival (OS) was 43% (95%CI: 28-57%) and 80 % (95%CI: 64-90%), respectively. Focusing on CR patients after ASCT and those who actually received BD consolidation, PFS adjusted for karyotype and age were not different between CR patients after ASCT and after BD consolidation, while patients with VGPR or less after consolidation had significantly lower PFS (Figure 3). [Conclusion] BD induction and ASCT provided CR rate of 27% among ASCT patients, although BD induction may expectedly cause adverse events including persistent neuropathy and viral infections. Patients who achieved CR after ASCT showed good PFS, and targeting CR through BD consolidation might improve CR rate. It is worthwhile to prospectively compare the efficacy of BD consolidation only for patients who failed to achieve CR or universal consolidation strategy. Disclosures Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding.

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Weekly Topotecan for Recurrent Ovarian, Fallopian Tube and Primary Peritoneal Carcinoma: Tolerability and Efficacy Study—The Israeli Experience

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e3182866944 ◽

2013 ◽

Vol 23 (3) ◽

pp. 475-480 ◽

Cited By ~ 5

Author(s):

Tamar Safra ◽

Tara Berman ◽

Adelya Yachnin ◽

Ilan Bruchim ◽

Mihai Meirovitz ◽

...

Keyword(s):

Overall Survival ◽

Partial Response ◽

Clinical Benefit ◽

Response Rate ◽

Progression Free Survival ◽

Complete Response ◽

Free Survival ◽

Platinum Sensitive ◽

Tubal Cancer ◽

Grade 3

ObjectivesThe purpose of this study was to assess the clinical activity and toxicity of weekly topotecan in a large cohort of epithelial ovarian (EOC), primary peritoneal (PPC), and tubal cancer patients.MethodsRecords of patients with recurrent EOC, PPC, and tubal cancer who were treated with weekly topotecan (4.0 mg/m2 on days 1, 8, and 15 on a 28-day cycle) after failure of more than 1 prior regimen were retrospectively reviewed in 8 centers in Israel.ResultsTwo hundred four patients were evaluated for efficacy and toxicity. Median age was 62 years (range, 27–89 years); 121 (59.3%) were platinum sensitive. Patients were exposed to a median of 2 previous lines (range, 1–9), and 48.5% received only 1 prior chemotherapy regimen. Median follow-up was 15.5 months (range, 2.5–112 months). Overall response rate was 26.5%, of which 11 patients (5.4%) had complete response, and 43 patients (21.1%) had partial response. Clinical benefit rate (complete response + partial response + stable disease) was 65.7%. Median progression-free survival was 4.0 months (95% confidence interval [CI], 3.5–4.5 months). There was no significant difference between platinum-sensitive and platinum-resistant patients regarding response rate or progression-free survival. Median overall survival from disease diagnosis was 45.0 months (95% CI, 40.04–49.6 months) and 16.0 months (95% CI, 12.3–19.7 months) from initiation of topotecan therapy. Overall survival was significantly different between patients with platinum-sensitive and platinum-resistant disease (19.9 vs 10.8 months, respectively, P = 0.003; 95% CI, 8.1–16.3 months). Multivariate analysis showed that only platinum sensitivity and topotecan line were associated with overall survival. Weekly topotecan was well tolerated—with only 16.7% of patients experiencing grade 3 to 4 hematologic toxicities. There were no other grade 4 toxicities, and only 6.9% grade 3 toxicities.ConclusionsIn this large cohort of recurrent EOC, PPC, and tubal cancer, weekly topotecan was well tolerated with good clinical benefit rate, comparable to previous studies.

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Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma

Blood ◽

10.1182/blood-2018-09-874396 ◽

2019 ◽

Vol 133 (18) ◽

pp. 1953-1963 ◽

Cited By ~ 26

Author(s):

Thierry Facon ◽

Jae Hoon Lee ◽

Philippe Moreau ◽

Ruben Niesvizky ◽

Meletios Dimopoulos ◽

...

Keyword(s):

Multiple Myeloma ◽

Response Rate ◽

Residual Disease ◽

Progression Free Survival ◽

Complete Response ◽

Newly Diagnosed ◽

Free Survival ◽

Intention To Treat ◽

Significant Difference ◽

Grade 3

Abstract The phase 3 CLARION study compared carfilzomib-melphalan-prednisone (KMP) with bortezomib-melphalan-prednisone (VMP) in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. Patients were randomized 1:1 to KMP or VMP for nine 42-day cycles (C). Patients received carfilzomib on days (D) 1, 2, 8, 9, 22, 23, 29, 30 (20 mg/m2: C1D1, C1D2; 36 mg/m2 thereafter) or bortezomib on D1, 4, 8, 11, 22, 25, 29, 32 (1.3 mg/m2; D4, 11, 25, 32 omitted for C5-9). Melphalan (9 mg/m2) and prednisone (60 mg/m2) were administered on D1-4. The primary endpoint was progression-free survival (PFS). Nine hundred fifty-five patients were randomized (intention-to-treat population: KMP, n = 478; VMP, n = 477). Median PFS was 22.3 months with KMP vs 22.1 months with VMP (hazard ratio [HR], 0.906; 95% confidence interval [CI], 0.746-1.101; P = .159). Median overall survival was similar and not reached in either group (HR, 1.08; 95% CI, 0.82-1.43). Overall response rate was 84.3% for KMP and 78.8% for VMP. Complete response rate was 25.9% for KMP and 23.1% for VMP. Minimal residual disease–negative rates were 15.7% (KMP) and 15.5% (VMP). Adverse events (AEs) of interest (any grade) occurring with a ≥5% higher patient incidence in the KMP arm were acute renal failure (13.9% [KMP] vs 6.2% [VMP]) and cardiac failure (10.8% vs 4.3%). Grade ≥3 AE rates were 74.7% (KMP) and 76.2% (VMP). Grade ≥2 peripheral neuropathy was lower for KMP vs VMP (2.5% vs 35.1%). Treatment with KMP in CLARION did not yield a statistically significant difference in PFS vs VMP. This trial was registered at www.clinicaltrials.gov as #NCT01818752.

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Phase II/III Trial of Etoposide and High-Dose Ifosfamide in Newly Diagnosed Metastatic Osteosarcoma: A Pediatric Oncology Group Trial

Journal of Clinical Oncology ◽

10.1200/jco.2002.20.2.426 ◽

2002 ◽

Vol 20 (2) ◽

pp. 426-433 ◽

Cited By ~ 67

Author(s):

Allen M. Goorin ◽

Michael B. Harris ◽

Mark Bernstein ◽

William Ferguson ◽

Meenakshi Devidas ◽

...

Keyword(s):

Response Rate ◽

Progression Free Survival ◽

Complete Response ◽

World Health ◽

High Dose ◽

Newly Diagnosed ◽

Free Survival ◽

Metastatic Osteosarcoma ◽

Health Organization ◽

Metastatic Sites

PURPOSE: The objectives of this trial were to estimate the response rate, progression-free survival, and overall survival of patients who received therapy with etoposide and high-dose ifosfamide, and to define the toxicity of this combination when provided with standard chemotherapy in patients with newly diagnosed metastatic osteosarcoma. PATIENTS AND METHODS: Eligible patients received infusions of 100 mg/m2 per day of etoposide and 3.5 g/m2 per day of ifosfamide for 5 days. Therapy with granulocyte colony-stimulating factor was begun on day 6. This was repeated 3 weeks after therapy was begun. Response was determined at week 6 by both standard World Health Organization response criteria and by pathologic determination of tumor necrosis of the primary tumor. RESULTS: Forty-three patients were registered; 39 were assessable for response and 41 for toxicity and survival. Twenty-eight (68%) of 41 had metastatic sites only in the lung; 12 (29%) had metastatic sites in other bones with or without lung involvement. Four patients (10%) experienced complete response, and 19 patients (49%) experienced partial response, for an overall response rate of 59% ± 8%. The projected 2-year progression-free survival (PFS) for the 28 patients with metastases to lungs was 39% ± 11%. The projected 2-year PFS for the 12 patients with metastases to other bones (with or without pulmonary metastases) was 58% ± 17%. Two patients died as a result of therapy toxicity. Eighty-three percent of patients had grade 4 neutropenia, and 29% had grade 4 thrombocytopenia. Ten patients (24%) had sepsis. Fanconi’s syndrome was observed in five patients. CONCLUSION: The combination of etoposide and high-dose ifosfamide is effective induction chemotherapy for patients with metastatic osteosarcoma, despite significant associated myelosuppression sometimes complicated by infection and renal toxicity.

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Phase III Study of the Value of Thalidomide Added to Melphalan Plus Prednisone in Elderly Patients With Newly Diagnosed Multiple Myeloma: The HOVON 49 Study

Journal of Clinical Oncology ◽

10.1200/jco.2009.26.1610 ◽

2010 ◽

Vol 28 (19) ◽

pp. 3160-3166 ◽

Cited By ~ 197

Author(s):

Pierre Wijermans ◽

Martijn Schaafsma ◽

Fabian Termorshuizen ◽

Rianne Ammerlaan ◽

Shulamiet Wittebol ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Elderly Patients ◽

Response Rate ◽

Progression Free Survival ◽

Phase Iii ◽

Newly Diagnosed ◽

Phase Iii Trial ◽

Free Survival ◽

Intent To Treat

Purpose For several decades, the treatment of elderly patients with multiple myeloma (MM) has consisted of melphalan and prednisone (MP). The Dutch-Belgium Hemato-Oncology Cooperative Group (HOVON) investigated the efficacy of thalidomide added to MP (MP-T) in a randomized phase III trial. The objective of this study was to investigate the efficacy, toxicity, and effects on quality of life of MP-T. Patients and Methods A randomized phase III trial compared standard MP with MP-T (thalidomide 200 mg/d) in newly diagnosed patients with multiple myeloma older than age 65 years. Maintenance therapy with thalidomide 50 mg/d was administered to patients after MP-T until relapse. The primary end point was event-free survival (EFS); response rate, overall survival (OS), and progression-free survival (PFS) were secondary end points. Results An intent-to-treat analysis of 333 evaluable patients showed significantly higher response rates in MP-T–treated patients compared with MP-treated patients a response (≥ partial response: 66% v 45%, respectively; P < .001; and ≥ very good partial response [VGPR]: 27% v 10%, respectively; P < .001). EFS was 13 months with MP-T versus 9 months with MP (P < .001). OS was 40 months with MP-T versus 31 months with MP (P = .05). Conclusion This study demonstrates that thalidomide improves the response rate and VGPR in elderly patients with newly diagnosed MM. MP-T also results in a better EFS, PFS, and OS.

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Phase III Study of Intravenous Vinorelbine in Combination With Epirubicin Versus Epirubicin Alone in Patients With Advanced Breast Cancer: A Scandinavian Breast Group Trial (SBG9403)

Journal of Clinical Oncology ◽

10.1200/jco.2004.11.503 ◽

2004 ◽

Vol 22 (12) ◽

pp. 2313-2320 ◽

Cited By ~ 46

Author(s):

Bent Ejlertsen ◽

Henning T. Mouridsen ◽

Sven T. Langkjer ◽

Jorn Andersen ◽

Johanna Sjöström ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Response Rate ◽

Complete Response Rate ◽

Metastatic Breast ◽

Progression Free Survival ◽

Complete Response ◽

Phase Iii ◽

Severe Toxicity ◽

Free Survival

Purpose To determine whether the addition of intravenous (IV) vinorelbine to epirubicin increased the progression-free survival in first-line treatment of metastatic breast cancer. Patients and Methods A total of 387 patients were randomly assigned to receive IV epirubicin 90 mg/m2 on day 1 and vinorelbine 25 mg/m2 on days 1 and 8, or epirubicin 90 mg/m2 IV on day 1. Both regimens were given every 3 weeks for a maximum of 1 year but discontinued prematurely in the event of progressive disease or severe toxicity. In addition, epirubicin was discontinued at a cumulative dose of 1,000 mg/m2 (950 mg/m2 from June 1999). Prior anthracycline-based adjuvant chemotherapy and prior chemotherapy for metastatic breast cancer was not allowed. Reported results were all based on intent-to-treat analyses. Results Overall response rates to vinorelbine and epirubicin, and epirubicin alone, were 50% and 42%, respectively (P = .15). The complete response rate was significantly superior in the combination arm (17% v 10%; P = .048) as was median duration of progression-free survival (10.1 months v 8.2 months; P = .019). Median survival was similar in the two arms (19.1 months v 18.0 months; P = .50). Leukopenia related complications, stomatitis, and peripheral neuropathy were more common in the combination arm. The incidences of cardiotoxicity and constipation were similar in both arms. Conclusion Addition of vinorelbine to epirubicin conferred a significant advantage in terms of complete response rate and progression-free survival, but not in terms of survival.

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ABVD Versus Modified Stanford V Versus MOPPEBVCAD With Optional and Limited Radiotherapy in Intermediate- and Advanced-Stage Hodgkin's Lymphoma: Final Results of a Multicenter Randomized Trial by the Intergruppo Italiano Linfomi

Journal of Clinical Oncology ◽

10.1200/jco.2005.02.907 ◽

2005 ◽

Vol 23 (36) ◽

pp. 9198-9207 ◽

Cited By ~ 133

Author(s):

Paolo G. Gobbi ◽

Alessandro Levis ◽

Teodoro Chisesi ◽

Chiara Broglia ◽

Umberto Vitolo ◽

...

Keyword(s):

Adjuvant Radiotherapy ◽

Hodgkin’S Lymphoma ◽

Response Rate ◽

Survival Rates ◽

Progression Free Survival ◽

Complete Response ◽

Hodgkin's Lymphoma ◽

Free Survival ◽

Drug Doses ◽

Advanced Hodgkin’S Lymphoma

Purpose In this multicenter, prospective, randomized clinical trial on advanced Hodgkin's lymphoma (HL), the efficacy and toxicity of two chemotherapy regimens, doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) and mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine (MOPPEBVCAD), were compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as standard therapy to select which regimen would best support a reduced radiotherapy program, which was limited to ≤ two sites of either previous bulky or partially remitting disease (a modification of the original Stanford program). Patients and Methods Three hundred fifty-five patients with stage IIB, III, or IV HL were randomly assigned. Three hundred thirty-four patients were assessable for the study and received six cycles of ABVD (n = 122), three cycles of Stanford V (n = 107), or six cycles of MOPPEBVCAD (n = 106); radiotherapy was administered to 76, 71, and 50 patients in these three arms, respectively. Results The complete response rates for ABVD, Stanford V, and MOPPEBVCAD were 89%, 76% and 94%, respectively; 5-year failure-free survival (FFS) and progression-free survival rates were 78%, 54%, 81% and 85%, 73%, and 94%, respectively (P < .01 for comparison of Stanford V with the other two regimens). Corresponding 5-year overall survival rates were 90%, 82%, and 89% for ABVD, Stanford V, and MOPPEBVCAD, respectively. Stanford V was more myelotoxic than ABVD but less myelotoxic than MOPPEBVCAD, which had larger reductions in the prescribed drug doses. Conclusion When associated with conditioned and limited (not adjuvant) radiotherapy, ABVD and MOPPEBVCAD were superior to Stanford V chemotherapy in terms of response rate and FFS and progression-free survival. Patients were irradiated less often after MOPPEBVCAD, but this regimen was more toxic. ABVD is still the best choice when it is combined with optional, limited irradiation.

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Weekly Carfilzomib, Cyclophosphamide and Dexamethasone (wCCyd) in Elderly Newly Diagnosed Multiple Myeloma Patients: Results of a Phase 2 Study

Blood ◽

10.1182/blood.v126.23.1828.1828 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1828-1828 ◽

Cited By ~ 2

Author(s):

Sara Bringhen ◽

Davide Rossi ◽

Alessandra Larocca ◽

Paolo Corradini ◽

Piero Galieni ◽

...

Keyword(s):

Partial Response ◽

Adverse Events ◽

Board Of Directors ◽

Phase 1 ◽

Progression Free Survival ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Phase 2 ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Background Carfilzomib is a novel second generation proteasome-inhibitor with significant anti-MM activity and favorable toxicity profile. In a recent phase 1/2 study in relapsed/refractory patients (pts) a weekly schedule of carfilzomib in combination with dexamethasone showed to be effective (overall response rate of 77%) and safe (ASCO 2015). The ongoing phase 3 ARROW study is comparing once- with twice-weekly carfilzomib. In the newly diagnosed setting, no data are available on weekly carfilzomib. We designed a phase 1/2 study of weekly carfilzomib in combination with cyclophosphamide and dexamethasone (wCCyd) for newly diagnosed MM pts. Results of the dose-escalation phase 1 portion of study were previously reported (Palumbo A et al, Blood 2014), the maximum tolerated dose of weekly carfilzomib was established as 70 mg/m2. Here we report efficacy and safety results of the phase 2 portion of the study. Methods Newly diagnosed pts ineligible for autologous stem-cell transplantation due to age or co-morbidities were enrolled in the phase 2 portion of the study. Pts received IV carfilzomib at the maximum tolerated dose 70 mg/m2 on days 1, 8, 15 combined with oral cyclophosphamide at 300 mg/m2 on days 1, 8, 15 and oral dexamethasone at 40 mg on days 1, 8, 15, 22, in 28-daycycles. After the completionof 9 cycles, pts received 28-day maintenance cycles with carfilzomib at 70 mg/m2 on days 1, 8, 15 until disease progression or intolerance. The primary objectives were to determine the efficacy and safety of wCCyd. The secondary objectives included the evaluation of time to progression, progression-free survival, time to next therapy and overall survival. Response was assessed according to the modified International Uniform Response Criteria. Adverse events (AEs) were graded following NCI-CTCAE v4. Results As of July 15, 2015, 47 newly diagnosed MM pts were enrolled in the phase 2 portion of the study. Median age was 72 years, 23% of pts were older than 75 years, 30% had ISS stage III, 34% had unfavorable FISH profile [t(4;14) or t (14;16) or del17p or amp1]. Toxicityand response data were available in 40 pts, who completed atleast the first cycle; 7 pts were still receiving their first cycle of treatment. Pts received a median of 6 cycles (range 1-9). Overall, 80% of pts achieved at least a partial response, 60% at least a very good partial response, and 28% a near complete response. Responses improved over time (Table 1). During the study, 9 pts progressed or died, the progression-free survival at 1 year was 75%. Grade (G) 3-4 drug-related adverse events included neutropenia (22%, 9 pts), thrombocytopenia (7%, 3 pts), infection (10%, 4 pts), acute pulmonary edema (5%, 2 pts), creatinine increase (5%, 2 pts), fever (2.5%, 1 pt), fatigue (2.5%, 1 pt) and headache (2.5%, 1 pt). G1-2 hypertension was reported in 6 pts (15%). No peripheral neuropathy was reported. Overall, the wCCyd regimen was well tolerated, 4 pts (10%) required carfilzomib dose-reduction (G3 hematologic toxicities [2 pts], G3 headache [1 pt] and G2 fatigue [1 pt]) and 9 pts (22%) required treatment discontinuation due to adverse events (2 infections, 1 acute pulmonary edema, 1 creatinine increase, 1 fever, 1 pt condition, 1 second tumor, 1 pericardial effusion, 1 sudden death). Conclusions This is the first prospective study evaluating once-weekly carfilzomib in treatment-naïve MM. wCCyd therapy appears safe and effective in newly diagnosed MM pts. Responses became deeper with subsequent cycles and toxicities were manageable. The response rate observed with weekly carfilzomib compares favorably with similar studies with standard twice-weekly carfilzomib infusion. Updated results will be presented at the meeting. Table 1. 2nd cycle 6th cycle 9th cycle Complete Response 17% 26% 33% At least near Complete Response 29% 39% 40% At least Very Good Partial Response 66% 82% 87% At least Partial Response 86% 87% 87% Disclosures Bringhen: Janssen-Cilag, Celgene, Novartis: Honoraria; Onyx: Consultancy; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use off-label of drugs for the dose and/or schedule and/or association. Larocca:Janssen-Cilag, Celgene: Honoraria. Offidani:Janssen-Cilag, Celgene, Sanofi, Amgen, Mundipharma: Honoraria. Gaidano:Celgene, Onyx: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Janssen-Cilag, Celgene, Onyx, Karyopharm: Honoraria, Research Funding; novartis: Honoraria. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria.

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Surgery of colorectal metastasis in the Optimox 1 study. A GERCOR Study

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3522 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3522-3522 ◽

Cited By ~ 2

Author(s):

N. Perez-Staub ◽

G. Lledo ◽

F. Paye ◽

B. Gayet ◽

M. Flesch ◽

...

Keyword(s):

Median Overall Survival ◽

Response Rate ◽

Disease Free Survival ◽

Complete Response ◽

Additional Benefit ◽

Curative Intent ◽

Free Survival ◽

Before And After ◽

Unresectable Metastasis ◽

Disease Free

3522 Background: Surgery of metastasis can cure arround 20% of metastatic colorectal cancer (MCRC) patients. The Optimox 1 study achieved a response rate over 50% with FOLFOX therapy in patients (pts) with initially unresectable metastasis which allowed to perform surgery in a significant number of pts (JCO 2006). We report here the results in pts who underwent surgery of metastasis (met). Methods: From jan 2000 to june 2002, 620 previously untreated patients with unresectable metastasis were randomized between FOLFOX4 every two weeks until progression (arm A), or FOLFOX7 for 6 cycles, maintenance without oxaliplatin for 12 cycles and reintroduction of FOLFOX7 (arm B). 101 pts were resected with a curative intent, 57 in arm A and 45 in arm B. Results: Patients characteristics were (arm A/B %): metachronous metastasis 77/51, liver met 82/91, lung met 16/11, other met 7/4, PAL < 3 ULN: 98/97, normal LDH: 52/51. 8% of pts achieved a complete response, 72% a partial response, 16% a stable disease. 89 pts had a single resection, 12 had a two-stage surgery. One patient died in arm B. Eleven pts who relapsed had a second surgery. Resection was radical (R0) for 71 pts (43 in arm A and 28 in arm B), 15 were R1 (margin invasion) and 15 were R2. R0/R1 patients had a median overall survival (OS) of 51 mo in arm A and 38 mo in arm B. Median disease-free survival (DFS) since surgery was 12 mo in arm A and 9 mo in arm B, with no statistical difference. 32% of R0/R1 pts were alive with no progression at 3 years in arm A and 20% in arm B. Median time from randomization to surgery was 8 mo. No difference was found between patients resected before 8 mo (n = 50) and after (n = 37) in OS (39 vs 45 mo, p = .67) nor in DFS (11.6 vs 9.5 mo, p = .24). Neither in pts resected before and after 6 mo in OS (p = .77) and DFS (p = .44). Conclusions: FOLFOX treatment allowed 14 % of unresectable patients to be rescued by surgery. There was no additional benefit to perform surgery after 6 months of therapy compared to early surgery. [Table: see text]

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