Final Results Of a Phase I Study Of The Anti-CD79b Antibody-Drug Conjugate DCDS4501A In Relapsed Or Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (NHL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4400-4400 ◽  
Author(s):  
Maria Corinna Palanca-Wessels ◽  
Gilles Andre Salles ◽  
Myron S. Czuczman ◽  
Sarit E. Assouline ◽  
Ian W. Flinn ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
B Cell ◽  
Research Funding ◽  
Phase I Study ◽  
Sensory Neuropathy ◽  
Peripheral Sensory Neuropathy ◽  
Antibody Drug Conjugate ◽  
Grade 3 ◽  
Peripheral Sensory ◽  
Antibody Drug

Abstract Background DCDS4501A (DCDS), an anti-CD79b monoclonal antibody (Ab), is conjugated to the anti-mitotic agent MMAE. We previously determined a recommended Phase II dose (RP2D) of 2.4 mg/kg every 21 days (q21d), and clinical activity in R/R B-cell NHL at doses ≥ 1.8 mg/kg (Palanca-Wessels et al. ASH 2012). Here we update results from patients (pts) treated at 1.8 mg/kg and from the 2.4 mg/kg expansion cohort. Methods We evaluated ongoing safety, tolerability, pharmacokinetics (PK) and activity of DCDS with or without rituximab (RTX) at 375 mg/m2 q21d in pts with R/R DLBCL and indolent (i)NHL. Results Sixty pts were treated with DCDS (6 at 1.8 mg/kg, 45 at 2.4 mg/kg) and DCDS+RTX (9, DCDS at 2.4 mg/kg). Median age 68 yrs (range 20-86); 82% ECOG PS<2; median 4 prior regimens (range 1-14); 97% had prior RTX; 28% had prior autologous stem cell transplant. The DCDS+RTX safety profile did not differ from DCDS monotherapy. Patients received a median of 7 cycles (range 1-20) of DCDS and 10 cycles (range 1-17) of DCDS + RTX; 18 patients continue to receive study treatment. Treatment-emergent adverse events (TEAEs) included neutropenia (50%), diarrhea (45%), nausea (40%), pyrexia (38%), peripheral neuropathy (25%), peripheral sensory neuropathy (20%), and hypokalemia (20%). Grade ≥ 3 AEs in ≥5% of pts included neutropenia (43%), anemia (13%), thrombocytopenia (7%), hyperglycemia (7%), fatigue (5%) and diarrhea (5%). Grade ≥ 3 infection was reported in 8 (13%) pts. Twenty-two (37%) pts reported a serious AE. TEAEs related to peripheral neuropathy (PN) were reported in 32 (53%) pts with median time to first onset of 63 days. 22/32 pts (69%) had worsening PN with median time to worsening of 49 days. Grade ≥ 3 peripheral neuropathy/peripheral sensory neuropathy/peripheral motor neuropathy was reported in 5 (8%) patients. PN was managed with dose delays and dose reductions resulting in complete reversal in 7 (22%) pts. Treatment discontinuations for AEs were reported in 25 (42%) pts including 17 for PN. Seven pts (12%) had ≥ 1 dose reduction including 3 for PN and 2 for neutropenia. Twenty-six patients (43%) had ≥ 1 dose delay including 14 for neutropenia and 6 for PN. Six deaths were reported within 60 days of last study treatment assessed as unrelated to DCDS. Exposure of Ab-conjugated (ac) MMAE, total Ab, and unconjugated MMAE increased with dose. Maximal concentrations of unconjugated MMAE were >100-fold lower than acMMAE with an average Cycle 1 value of 5-9 ng/mL at the 2.4 mg/kg ADC dose level. Moderate accumulation of acMMAE and total Ab on the q21d dosing schedule was observed with no accumulation of free MMAE. Overall objective responses were observed in 27/51 (53%) DCDS and 7/9 (78%) DCDS+RTX pts. Objective (OR) and complete responses (CR) by histology were as follows: The median PFS for DLBCL patients treated with DCDS or DCDS + RTX was 149 days. The median PFS for iNHL patients treated with DCDS or DCDS + RTX was 241 days. Conclusions DCDS and DCDS+RTX were generally well-tolerated. Neutropenia and PN were the principal toxicities. PN was reversible in some patients with dose delays and reductions. Encouraging anti-tumor activity was observed in heavily pretreated pts with R/R NHL. Updated results from this Phase I study will be presented. An ongoing randomized Phase II study of DCDS+RTX versus a CD22-directed ADC (DCDT2980S) with the same linker-cytotoxic agent in patients with R/R DLBCL and follicular lymphoma will further assess the efficacy of DCDS in the treatment of NHL. Additional studies of DCDS combined with immunochemotherapy are being planned. Disclosures: Palanca-Wessels: Genentech, inc.: Research Funding. Off Label Use: anti-CD79b Antibody-Drug Conjugate in r/r B-cell NHL. Salles:Genentech, inc.: Consultancy. Czuczman:Genentech, inc.: Consultancy, Honoraria. Flinn:Genentech, inc.: Research Funding. Sehn:Genentech, inc.: Consultancy, Honoraria, Research Funding. Tilly:Genentech, inc.: Honoraria. Advani:Genentech, inc.: Research Funding. Casasnovas:Genentech, inc.: Research Funding. Press:Genentech, inc.: Consultancy, Research Funding. Yalamanchili:Genentech, inc.: Employment. Kahn:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Chai:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment. Morschhauser:Genentech, inc.: Honoraria, Research Funding.

Final Results Of a Phase I Study Of The Anti-CD22 Antibody-Drug Conjugate (ADC) DCDT2980S With Or Without Rituximab (RTX) In Patients (Pts) With Relapsed Or Refractory (R/R) B-Cell Non-Hodgkin’s Lymphoma (NHL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4399-4399 ◽  
Author(s):  
Ranjana Advani ◽  
Andy I. Chen ◽  
Daniel Lebovic ◽  
Mark W. Brunvand ◽  
Andre Goy ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Phase I ◽  
B Cell ◽  
Median Time ◽  
Research Funding ◽  
Phase I Study ◽  
Single Agent ◽  
Antibody Drug Conjugate ◽  
Grade 3 ◽  
Antibody Drug

Abstract Background DCDT2980S (DCDT) is an anti-CD22 monoclonal antibody (Ab) conjugated to MMAE, a potent anti-microtubule inhibitor. We have previously reported clinical activity and acceptable toxicity in pts with R/R B-cell NHL treated at DCDT doses of 1.8 and 2.4 mg/kg. The maximum tolerated dose (MTD) was defined as 2.4 mg/kg either as a single agent or in combination with RTX (375 mg/m2) every 21 days (q21d) (Advani et al. ASH 2012, abstract 59). In this report, we provide updated results from pts treated at 1.8 mg/kg as well as an expanded cohort treated at 2.4 mg/kg. Methods We evaluated safety, tolerability, pharmacokinetics (PK), and activity of DCDT q21d with or without RTX (375 mg/m2) in pts with R/R B-cell NHL. Expanded cohorts of pts with R/R diffuse large cell lymphoma (DLBCL) or indolent (i)NHL were evaluated at the single-agent MTD of 2.4 mg/kg q21d. Results Forty-six pts enrolled in DCDT ≥ 1.8 mg/kg (7 at 1.8 mg/kg, 39 at 2.4 mg/kg) and 16 in the DCDT+RTX cohort (5 at 1.8 mg/kg, 11 at 2.4 mg/kg). Median age was 66 yrs; 92% had an ECOG PS<2; median of 3 prior regimens (range 1-11); 100% prior RTX, 8% prior stem cell transplant. Patients received a median of 5 cycles (range 1, 24) of DCDT and 6 cycles (range 1, 15) of DCDT + RTX; 7 patients continue to receive study treatment. The DCDT+RTX safety profile did not differ from DCDT monotherapy and toxicities were mostly Grade 1-2. Grade ≥ 3 treatment-emergent adverse events (TEAEs) in ≥5% of pts included neutropenia (26%), hyperglycemia (10%), peripheral sensory neuropathy (10%), fatigue (5%), and diarrhea (5%). Febrile neutropenia and Grade 3-4 infection occurred in 1 pt and 7 pts respectively. The median time to first onset peripheral neuropathy (PN) was 50 days. Worsening PN (at least one grade increase) occurred in 18/33 pts (55%) with median time to worsening of 48 days. PN was managed with dose delays and dose reductions resulting in complete reversal in 5 (15%) pts. Serious AEs were seen in 37% of pts, the most common (≥ 3 pts) included pyrexia (3), pneumonia (3) and dyspnea (3). Treatment discontinuations for AEs were reported in 16 (26%) pts including 12 for peripheral neuropathy. Twenty-four pts (39%) had at least one dose delay including 10 for neutropenia and 5 for peripheral neuropathy. Twelve pts (19%) had at least one dose reduction including 8 for peripheral neuropathy and 7 for neutropenia. Three deaths occurring within 60 days of the last dose of DCDT judged unrelated to DCDT were reported. Exposure of Ab-conjugated (ac) MMAE, total Ab, and unconjugated MMAE increased with dose. Maximal concentrations of unconjugated MMAE were >100-fold lower than acMMAE with average Cycle 1 value of 5-7 ng/mL at the 2.4 mg/kg ADC dose level. Moderate accumulation of acMMAE and total Ab on the q21d dosing schedule was observed with no accumulation of free MMAE. Concurrent RTX administration did not impact DCDT PK. Overall objective responses were observed in 19/46 (41%) DCDT and 5/16 (31%) DCDT+RTX pts. Objective (OR) and complete responses (CR) by histology were as follows: The median PFS for DLBCL patients treated with DCDT or DCDT + RTX was 115 days. The median PFS for iNHL patients treated with DCDT or DCDT + RTX was 227 days. Conclusions DCDT alone or combined with RTX was generally well-tolerated. PN and neutropenia are the principal toxicities associated with DCDT. PN was reversible in some patients with dose delays and reductions. Encouraging antitumor activity was observed in heavily pre-treated pts with R/R NHL. Updated results from this Phase I study will be presented. The addition of rituximab does not appear to enhance the efficacy of DCDT based on the small number of patients treated with the combination and continues to be evaluated in an ongoing randomized Phase II study in patients with R/R DLBCL and FL of DCDT+RTX versus a CD79b-directed ADC (DCDS4501A) with the same linker-cytotoxic agent. Additional studies of DCDT combined with immunochemotherapy are planned. Disclosures: Advani: Genentech, inc.: Research Funding. Off Label Use: Anti-CD22 Antibody-Drug Conjugate. Chen:Genentech, inc.: Consultancy, Research Funding. Lebovic:Genentech, inc.: Speakers Bureau. Brunvand:Genentech, inc.: Speakers Bureau. Goy:Genentech, inc.: Research Funding. Chang:Genentech, inc.: Research Funding. Hochberg:Genentech, inc.: Consultancy. Yalamanchili:Genentech, inc.: Employment. Kahn:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Chai:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment.

scholarly journals Results of an Ongoing Phase 2 Study of Brentuximab Vedotin with Rchp As Frontline Therapy in Patients with High-Intermediate/High-Risk Diffuse Large B Cell Lymphoma (DLBCL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 104-104 ◽  
Author(s):  
Lihua E. Budde ◽  
Ahmad Halwani ◽  
Christopher A. Yasenchak ◽  
Charles Michael Farber ◽  
John M Burke ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
High Risk ◽  
Research Funding ◽  
Sensory Neuropathy ◽  
Brentuximab Vedotin ◽  
Peripheral Sensory Neuropathy ◽  
Genetics Research ◽  
Equity Ownership ◽  
Grade 3 ◽  
Peripheral Sensory

Abstract Introduction DLBCL is the most common lymphoid neoplasm in adults (Swerdlow 2016). While durable CRs are achieved in approximately 70% of patients (pts) with frontline RCHOP therapy (Pfreundschuh 2008), pts with high-risk features often experience disease resistance or relapse. In Part 1 of an ongoing study, pts with high-intermediate or high risk DLBCL by international prognostic index (IPI) scores, regardless of CD30 expression by IHC, were treated with 1.2 or 1.8 mg/kg brentuximab vedotin (BV) combined with RCHOP. After 3 of the first 10 pts treated at 1.8 mg/kg BV+RCHOP developed Grade 3 peripheral neuropathy (per Standardized MedDRA Query [SMQ]), all pts enrolled subsequently received treatment with 1.2 mg/kg BV+RCHOP. Following completion of enrollment in Part 1, the protocol was amended to enroll a non-randomized portion of the study (Part 2) evaluating the safety and efficacy of 1.8 mg/kg BV+RCHP (Yasenchak 2015), followed by an open-label, randomized portion comparing BV+RCHP to RCHOP (Part 3). Initial results from Part 2 and updated results from Part 1 are reported here. Methods For Part 2 of the study, pts with CD30-expressing high-intermediate and high-risk DLBCL were treated with up to 6 cycles of 1.8 mg/kg BV+RCHP (NCT01925612). Key inclusion criteria were CD30 expression by IHC performed by a local pathology lab and standard IPI scores of 3-5 or age-adjusted IPI (aaIPI) scores of 2-3 (high-intermediate/high risk). CD30 expression was confirmed by a central pathology lab, although CD30 expression by local pathology lab was required for eligibility. Disease response was evaluated with PET/CT per Cheson 2007. Results At the time of analysis for this ongoing study, 11 pts in Part 2 were treated with BV+RCHP (7 male, 4 female; 22-78 yrs). Of these pts, 9 had high-intermediate risk (IPI 3, aaIPI 2) and 2 had high risk disease (IPI 4-5, aaIPI 3), 6 had Stage IV disease, and 6 had an ECOG score of 2. At the end of treatment, the overall response rate was 91% (9 CR, 1 PR); 1 pt had PD after Cycle 4. The most frequent (>20%) treatment-emergent adverse events (AEs) were alopecia and nausea (73% each); fatigue (64%); constipation and peripheral sensory neuropathy (55% each); neutropenia and throat irritation (36% each); and chills, diarrhea, headache, and stomatitis (27% each). Grade 3 or 4 AEs occurred in 8 pts and 5 pts had serious AEs, which included febrile neutropenia, bacteremia, nausea, pneumocystis jiroveci pneumonia, pulmonary embolism, and vomiting. Peripheral sensory neuropathy occurred in 6 pts and all were Grade 1 or 2 events; no peripheral motor neuropathy AEs were reported. No AEs were fatal or led to discontinuation. One pt discontinued treatment after Cycle 4 due to disease progression. For the first 51 pts in Part 1, the progression-free survival (PFS) at 18 months for pts with CD30 expression (25 pts) or without detectable CD30 expression (24 pts) by IHC was 79% (95% CI: 57%, 91%) versus 58% (95% CI: 36%, 75%), respectively. Overall survival for pts was 92% (95% CI: 71%, 98%) versus 71% (95% CI: 48%, 85%), respectively. Ten pts had pre-existing peripheral neuropathy (per SMQ) at study entry. Treatment-emergent peripheral neuropathy (per SMQ) was observed in 75% of pts (38/51) who received BV+RCHOP; 55% of these pts (21/38) had resolution of all or some peripheral neuropathy events. Conclusions 1.8 mg/kg BV+RCHP is active as frontline treatment in CD30-expressing, high-intermediate/high risk DLBCL. When combined with RCHP, 1.8 mg/kg BV appears to be well-tolerated. The PFS and OS for pts with CD30-expression who received BV+RCHOP appear promising. The study is currently ongoing in pts with CD30-expressing high-intermediate/high risk DLBCL to assess the safety and activity of 1.8 mg/kg BV+RCHP versus standard RCHOP. Disclosures Halwani: Bristol Myers-Squibb: Research Funding; Kyowa Hakko Kirin: Research Funding; Takeda: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Other: Travel Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Miragen: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding. Yasenchak:Seattle Genetics: Research Funding. Farber:Seattle Genetics: Research Funding. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Fayad:Seattle Genetics: Consultancy, Research Funding. Holkova:Seattle Genetics: Research Funding. Knapp:Insys Therapeutics, Inc.: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; janssen: Research Funding; GSK: Research Funding; Genentech: Research Funding; Acerta: Research Funding. Patel-Donnelly:Seattle Genetics: Research Funding. Yimer:Ariad Pharmaceuticals: Consultancy; Biotheranostics: Consultancy; Bluebird Bio: Equity Ownership; Kite Pharma: Equity Ownership; Clovis Oncology: Equity Ownership; Juno Therpeutics: Equity Ownership; Seattle Genetics: Research Funding. Smith:Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding. Levy:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau; Seattle Genetics: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding. Seetharam:Seattle Genetics: Research Funding. Belada:Seattle Genetics: Research Funding. Brooks:Seattle Genetics: Research Funding. Kingsley:Gilead: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Wagner-Johnston:Seattle Genetics: Research Funding. Ruffner:Forma Therapeutics: Consultancy; Sydnax: Consultancy; Seattle Genetics: Employment, Equity Ownership; Array Biopharma: Employment; Medivation: Employment. Bartlett:Gilead: Consultancy.

A Phase I Study of DCDT2980S, an Antibody-Drug Conjugate (ADC) Targeting CD22, in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (NHL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 59-59 ◽  
Author(s):  
Ranjana Advani ◽  
Daniel Lebovic ◽  
Mark Brunvand ◽  
Andy I. Chen ◽  
Andre Goy ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Antibody Drug Conjugate ◽  
Safety And Efficacy ◽  
Grade 3 ◽  
Dose Levels ◽  
Anti Tumor Activity

Abstract Abstract 59 Introduction: CD22 is a lineage marker expressed in most B-cell lymphomas. DCDT2980S is an ADC consisting of an anti-CD22 monoclonal antibody conjugated to monomethyl auristatin E (MMAE), a potent microtubule disrupting agent linked to the antibody via a protease-cleavable peptide linker. DCDT2980S exhibits potent anti-tumor activity in murine xenograft models of B-cell lymphoma and is being evaluated in a Phase I study to assess the safety, tolerability, pharmacokinetics (PK), and biologic activity in patients (pts) with relapsed/refractory B-cell NHL. Methods: Pts receive DCDT2980S intravenously every 21 days at dose levels 0.1 to 3.2 mg/kg until disease progression or unacceptable toxicity. Intrapatient dose escalation based on tolerability at higher doses is permitted. Following determination of the recommended Phase II dose (RP2D) based on protocol-defined dose-limiting toxicities (DLTs) occurring within 21 days of dosing, additional pts with indolent and aggressive B-cell NHL are being enrolled to further evaluate safety and efficacy based on Cheson response criteria. Here we report the RP2D and preliminary safety and efficacy results. Results: To date, 35 pts (57% male), median age 66 years (range 30–85) have been enrolled: diffuse large B-cell lymphoma (DLBCL, n=18), follicular lymphoma (FL, n=11), transformed FL (n=4), and small lymphocytic lymphoma (n=2). Enrolled patients were heavily pre-treated: 26 pts had received ≥ 3 prior regimens, all pts had received prior rituximab, and 7 pts received prior high-dose therapy followed autologous or allogenic stem cell transplantation. Overall, pts received a median of 4 doses (range 1–25) of DCDT2980S in 7 dose-escalation cohorts, and 2 expansion cohorts at the RP2D. All 3 pts treated with DCDT2980S at 3.2 mg/kg developed Grade 4 neutropenia following the first dose, one of which constituted a DLT. No DLTs were reported in the 6 pts treated at 2.4 mg/kg, which is the RP2D. Across all dose levels, the most common treatment-emergent adverse events (AE) in ≥ 20% of pts were diarrhea (34%), fatigue (34%), nausea (31%), neutropenia (26%), decreased appetite (23%), vomiting (23%), and peripheral edema (20%). Treatment-emergent Grade ≥ 3 AEs were reported in 9 (27%) pts including 5 out of 9 pts who were treated at the RP2D of 2.4 mg/kg. Overall, neutropenia (24%) was the only Grade ≥ 3 AE in ≥ 10% of pts (24%) and was the only Grade ≥ 3 AE reported in > 1 pt (n=2) treated at the RP2D. Eight (26%) pts across all dose levels experienced a serious AE (SAE) of which one Grade 3 dehydration in a pt treated at 3.2 mg/kg was attributed to DCDT2980S. Treatment discontinuation due to AEs occurred in 3 pts: Grade 3 neutropenia (n=1) and Grade 3 peripheral sensory neuropathy (n=2). No deaths were reported within 30 days of the last dose of DCDT2980S. Assessment of Cycle 1 PK after the first dose of DCDT2980S indicated that the exposure of antibody-conjugated MMAE (acMMAE), total antibody, and free MMAE increased with dose. The clearance estimates of both acMMAE and total antibody were similar across doses from 1.0–3.2 mg/kg. The volume of distribution estimates for acMMAE and total antibody approximated plasma volume and did not change with dose and suggest dose-proportional increase of acMMAE and total antibody exposures for doses of 1.0–3.2 mg/kg. Early evidence of anti-tumor activity was observed. At the RP2D of 2.4 mg/kg, 2 of 3 pts with DLBCL had > 75% reduction in tumor sum of perpendicular dimensions (SPD) and negative PET scans; 1 partial response was noted in a pt with FL treated at 1.8 mg/kg. These 3 pts continue on study, each having received at least 8 cycles of study treatment. Two additional pts with DLBCL receiving 0.5 mg/kg and 3.2–2.4 mg/kg had > 50% reduction in tumor SPD and discontinued study treatment after 8 and 6 cycles, respectively, to undergo stem cell transplant. Conclusions: In this early experience, DCDT2980S is well tolerated, has a favorable safety profile and has evidence of anti-tumor activity in in a heavily pretreated pts with relapsed/refractory B-cell NHL. Updated clinical data will be presented. These results support additional clinical evaluation of DCDT2980S in B-cell malignancies. Disclosures: Advani: Genentech: Research Funding. Off Label Use: anti-CD79b Antibody-Drug Conjugate (ADC) DCDS4501A. Lebovic:Genentech: Speakers Bureau. Brunvand:Genentech: Speakers Bureau. Chen:Genentech: Research Funding. Chang:Genentech: Research Funding. Ho:Genentech: Employment. Kahn:Genentech: Employment. Lu:Genentech: Employment. Su:Genentech: Employment. Chu:Genentech: Employment.

Preliminary Safety and Efficacy of the Combination of Brentuximab Vedotin and Ipilimumab in Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 585-585 ◽  
Author(s):  
Catherine S. Diefenbach ◽  
Fangxin Hong ◽  
Jonathon B. Cohen ◽  
Michael J. Robertson ◽  
Richard F. Ambinder ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Checkpoint Inhibitor ◽  
Sensory Neuropathy ◽  
Peripheral Sensory Neuropathy ◽  
Level 1 ◽  
Grade 3 ◽  
Peripheral Sensory ◽  
Level 2

Abstract Background: Despite advances in chemotherapy, R/R HL remains a significant clinical problem with over 1,000 primarily young lives lost annually. HL is a unique tumor in which a small number of malignant Hodgkin Reed-Sternberg (HRS) cells propagate an immunosuppressive microenvironment that augments HRS growth and survival. We hypothesized that immune checkpoint inhibitor therapy could activate the tumor immune microenvironment, while the CD30 expressing HRS cells could be targeted by brentuximab vedotin (BV), thereby overcoming tumor cell resistance and deepening clinical responses. E4412 is a phase 1 ECOG-ACRIN sponsored study of the combination of BV and the checkpoint inhibitors ipilimumab (IPI) and nivolumab (NIVO) in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). Here we report the data on the patients treated with BV + IPI, the first cohort of the study. Methods: Patients with biopsy proven R/R HL were treated with BV 1.8mg/kg and two escalating doses of IPI: 1 mg/kg or 3mg/kg. After safety was determined an expanded cohort was treated with BV 1.8mg/kg IV and IPI 3mg/kg IV. The schedule consisted of BV administered every 21 days for 16 cycles and IPI every 21 days x 4 doses and thereafter every 3 months for up to a year. Dose limiting toxicity (DLT) was defined for purposes of dose escalation within the first cycle of therapy. Patients are followed for toxicity up to 30 days beyond their last treatment. Results: As of 7/2015 19 of 23 planned patients have been treated with BV + IPI. We report the data on the full dose escalation population (13 patients: Dose level 1 (6), Dose level 2 (7)). The median age was 33 years (range: 20-49). Seven patients were male. Patients were heavily pretreated with a median of 4 prior therapies (2-13). Fourpatients had prior treatment with BV; 8 patients had prior SCT (7 autologous, 1 allogeneic). Safety: Overall the regimen of BV + IPI was extremely well tolerated with no DLTs noted during dose escalation. Toxicities considered at least possibly related to drug during any cycle of treatment are shown according to grade in Table 1. The most common treatment related adverse events were: diarrhea, rash, and peripheral sensory neuropathy. Other AEs of interest included: alopecia, transaminitis, and uveitis. Grade 3 and 4 treatment related adverse events (AEs) included: Dose level 1: one grade 3 infusion reaction, which led to a protocol amendment to include premedication, no further grade 3 infusion reactions were noted; Dose level 2: one each: grade 3 rash, vomiting, and peripheral sensory neuropathy, and one grade 4 thrombocytopenia in patient with pre-existing thrombocytopenia. Response: For the 12 evaluable patients, the overall response (ORR) for the combination of BV + IPI was 67% with a complete response (CR) rate of 42% (5 of 12 patients). An additional 2 patients had stable disease (SD) giving a clinical benefit rate of 83%. Three of 5 of the CRs occurred at dose level 1 (1mg dose of IPI). The median progression free survival (PFS) is 0.74 years with a median follow-up of 0.66 years. Conclusion: In this first reported study of the combination of checkpoint inhibitor and ADC, toxicity was low, primarily grades 1 and 2. In a heavily pretreated patient population, 33% of whom had had prior BV and 67% of whom were s/p ASCT, the ORR of 67% and CR rate of 42% suggests a potential deepening of response compared to monotherapy. More than half of these CRs occurred at 1mg of IPI suggesting that in combination with ADC, low doses of immune stimulation may be highly active. Optimization of this combination strategy is planned with ongoing accrual to cohorts receiving BV + NIVO, and BV + IPI + NIVO. Data will be updated to include the full BV + IPI cohort by the time of the annual meeting. Table 1. Common and Immune Toxicities Toxicity Type Dose Level 1 (n=6) Dose Level 2 (n=7) Grade Grade 1,2 3 4 5 1,2 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) Fatigue 5 - - - 3 - - - Fever 1 - - - 3 - - - Pain 2 - - - 3 - - - Alopecia 2 - - - 1 - - - Pruritus 1 - - - 2 - - - Rash maculo-papular 4 - - - 2 1 - - Diarrhea 4 - - - 4 - - - Dyspepsia 2 - - - 1 - - - Nausea 6 - - - 4 - - - Vomiting 3 - - - 2 1 - - Papulopustular rash 1 - - - 1 - - - Alanine aminotransferase increased 3 - - - 3 - - - Aspartate aminotransferase increased 3 - - - 2 - - - Platelet count decreased - - - - - - 1 - Anorexia 3 - - - - - - - Headache 2 - - - 2 - - - Peripheral sensory neuropathy 5 - - - 4 1 - - Dry eye 2 - - - - - - - Uveitis 1 - - - - - - - Cough 2 - - - 1 - - - Disclosures Diefenbach: Molecular Templates: Research Funding; Immunogen: Consultancy; Celgene: Consultancy; Idera: Consultancy; Jannsen Oncology: Consultancy; Gilead: Equity Ownership, Research Funding, Speakers Bureau; Incyte: Research Funding; Genentech: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Off Label Use: Presentation will discuss the experimental use of the checkpoint inhibitor Ipilimumab in relapsed/refractory Hodgkin lymphoma.. Cohen:Celgene: Consultancy; Millennium: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; BMS: Research Funding; Janssen: Research Funding. Robertson:Eli Lilly: Equity Ownership. Fenske:Pharmacyclics: Honoraria; Seattle Genetics: Honoraria; Millennium/Takeda: Research Funding; Celgene: Honoraria. Kahl:Roche/Genentech: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy; Cell Therapeutics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

A Phase I Study of the Anti-CD79b Antibody-Drug Conjugate (ADC) DCDS4501A Targeting CD79b in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (NHL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 56-56 ◽  
Author(s):  
Maria Corinna Palanca-Wessels ◽  
Ian W. Flinn ◽  
Laurie H. Sehn ◽  
Manish Patel ◽  
Randeep Sangha ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Target Lesion ◽  
Antibody Drug Conjugate ◽  
B Cell Malignancies ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract Abstract 56 Introduction: CD79b, a component of the B-cell receptor (BCR), is expressed by nearly all B-cell malignancies including NHL. DCDS4501A is an ADC consisting of an anti-CD79b monoclonal antibody conjugated to monomethyl auristatin E (MMAE), a microtubule disrupting agent via a protease-cleavable peptide linker. DCDS4501A exhibits potent anti-tumor activity in murine xenograft models of B-cell lymphoma. Methods: A Phase I study of DCDS4501A is being conducted to assess the safety, tolerability, pharmacokinetics (PK), and biologic activity of escalating doses of DCDS4501A in pts with relapsed/refractory B-cell NHL. Pts receive DCDS4501A intravenously every 21 days until disease progression or unacceptable toxicity. Intrapatient dose escalation based on tolerability at higher doses is permitted. Following determination of the recommended Phase II dose (RP2D) based on protocol-defined dose-limiting toxicities (DLTs) occurring within 21 days of dosing, additional pts with indolent and aggressive B-cell NHL will be enrolled to further evaluate safety and efficacy based on Cheson response criteria. Here we report the RP2D and preliminary safety and efficacy results. Results: To date, 33 pts have been enrolled (64% male), median age of 65 years (range 20–85): follicular lymphoma (FL, n=14), diffuse large B-cell lymphoma (DLBCL, n=11), MCL (n=4), MZL (n=2), transformed FL (n=1), and small lymphocytic lymphoma (SLL, n=1). Enrolled patients were heavily pre-treated: 29 patients had ≥ 3 prior regimens, all pts had received prior rituximab, and 9 pts received prior high-dose therapy followed by stem cell transplantation. Pts received a median of 3 doses (range 1–12) of DCDS4501A in 6 dose-escalation cohorts with doses ranging from 0.1–2.4 mg/kg. The protocol-specified MTD was not formally reached, however, 2.4 mg/kg DCDS4501A was determined to be the RP2D based on the overall safety and tolerability profile at that dose, which included 1 pt with a DLT of Grade 4 febrile neutropenia and pneumonia. The most common treatment-emergent adverse events (AE) occurring in ≥ 20% of pts were neutropenia (59%), diarrhea (38%), nausea (34%), hyperglycemia (31%), fatigue (31%), constipation (28%), peripheral neuropathy (28%), pyrexia (28%), leukopenia (25%), chills (22%), and cough (22%). Neutropenia (39%) and leukopenia (12%) were the only treatment-emergent Grade ≥ 3 AEs in ≥ 10% of pts. Seven of 12 pts treated at the RP2D of 2.4 mg/kg experienced a Grade 3–4 AE: Grade 3–4 neutropenia in 5 pts, and anemia, leukopenia and fatigue each in 2 pts. Eight (24%) pts across all dose levels experienced a serious AE (SAE). Four SAEs were reported in 2 pts treated at the RP2D of 2.4 mg/kg: 1 pt with atrial fibrillation, neutropenia, and pneumonia and 1 pt with cardiac failure; in both cases the SAE resolved and study treatment resumed. Treatment discontinuation due to AE occurred in 1 pt each for Grade 3 neutropenia and Grade 3 hyponatremia. One pt had a dose reduction for Grade 4 febrile neutropenia and pneumonia. No deaths were reported within 30 days of the last dose of DCDS4501A. Most cases of neutropenia were observed in the absence of growth factor support. Assessment of Cycle 1 PK after the first dose of DCDS4501A indicated that exposure of antibody-conjugated MMAE (acMMAE), total antibody, and free MMAE, increased with dose. The clearance estimates of acMMAE and total antibody were similar across doses from 0.1–2.4 mg/kg; volume of distribution estimates of acMMAE and total antibody approximated plasma volume, which also did not change with dose. These results suggested dose proportional increase of acMMAE and total antibody exposures. Early evidence of anti-tumor activity was observed, including 5 pts with > 50% reduction in target lesion burden at the first on-treatment tumor assessment after 3–4 cycles of treatment: 2 with FL, and 1 each with DLBCL, transformed FL, and MCL; 4 pts continue on treatment with DCDS4501A (range 5–12 cycles). Two of four pts treated at 2.4 mg/kg evaluable for anti-tumor activity to date had > 80% reduction in target lesion burden at the first on-treatment tumor assessment. Conclusions: DCDS4501A, a novel ADC targeting CD79b, has demonstrated an acceptable toxicity profile and encouraging anti-tumor activity in heavily pretreated pts with relapsed/refractory B-cell NHL. Updated clinical data will be presented. These results support additional clinical evaluation of DCDS4501A in B-cell malignancies. Disclosures: Palanca-Wessels: Genentech: Research Funding. Off Label Use: anti-CD79b Antibody-Drug Conjugate (ADC) DCDS4501A. Salles:roche: Consultancy. Morschhauser:Genentech: Honoraria. Advani:Genentech: Research Funding. Press:g: Consultancy. Ho:Genentech: Employment. Kahn:Genentech: Employment. Lu:Genentech: Employment. Su:Genentech: Employment. Chu:Genentech: Employment.

Efficacy and Safety of Ixabepilone (BMS-247550) in a Phase II Study of Patients With Advanced Breast Cancer Resistant to an Anthracycline, a Taxane, and Capecitabine

2007 ◽  
Vol 25 (23) ◽  
pp. 3407-3414 ◽  
Author(s):  
Edith A. Perez ◽  
Guillermo Lerzo ◽  
Xavier Pivot ◽  
Eva Thomas ◽  
Linda Vahdat ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Sensory Neuropathy ◽  
Efficacy And Safety ◽  
Peripheral Sensory Neuropathy ◽  
Metastatic Setting ◽  
Grade 3 ◽  
Peripheral Sensory

PurposeTo evaluate the efficacy and safety of ixabepilone in patients with metastatic breast cancer (MBC) resistant to anthracycline, taxane, and capecitabine, in this multicenter, phase II study.Patients and MethodsPatients with measurable disease who had tumor progression while receiving prior anthracycline, taxane, and capecitabine were enrolled. Ixabepilone 40 mg/m2monotherapy was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle. The primary end point was objective response rate (ORR), assessed by an independent radiology facility (IRF).ResultsA total of 126 patients were treated and 113 were assessable for response. Patients were heavily pretreated: 88% had received at least two lines of prior chemotherapy in the metastatic setting. IRF-assessed ORR was 11.5% (95% CI, 6.3% to 18.9%) for response-assessable patients. Investigator-assessed ORR for all treated patients was 18.3% (95% CI, 11.9% to 26.1%). Fifty percent of patients achieved stable disease (SD); 14.3% achieved SD ≥ 6 months. Median duration of response and progression-free survival were 5.7 and 3.1 months, respectively. Median overall survival was 8.6 months. Patients received a median of 4.0 treatment cycles (range, one to 16 cycles), and 25% of patients received ≥ eight cycles. Grade 3/4 treatment-related events included peripheral sensory neuropathy (14%), fatigue/asthenia (13%), myalgia (8%), and stomatitis/mucositis (6%). Resolution of grade 3/4 peripheral sensory neuropathy occurred after a median period of 5.4 weeks.ConclusionIxabepilone demonstrated clear activity and a manageable safety profile in patients with MBC resistant to anthracycline, taxane, and capecitabine. Responses were durable and notable in patients who had not previously responded to multiple prior therapies.

scholarly journals Preliminary Results of a Phase I Study of Obinutuzumab, Venetoclax, and Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4185-4185 ◽  
Author(s):  
Kami J. Maddocks ◽  
Farrukh T. Awan ◽  
Ying Huang ◽  
Sabarish Ayyappan ◽  
Robert A Baiocchi ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Phase I Study ◽  
Hematologic Toxicity ◽  
Tumor Lysis ◽  
Genetics Research ◽  
Non Hodgkin Lymphoma ◽  
Grade 3

Abstract Introduction: Combined obinutuzumab (O) and lenalidomide (L) has demonstrated safety and preliminary efficacy in follicular lymphoma1. Venetoclax (V), a BCL2 inhibitor, as a single agent2 and in combination with rituximab3 is under development in several subtypes of B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of O, V, and L to determine the maximum tolerated dose, dose-limiting toxicities (DLT), and preliminary efficacy. Methods: Pts with relapsed/refractory diffuse large B-cell (DLBCL), transformed, high grade B-cell, Burkitt, marginal zone, and follicular (FL) lymphoma who have received ≥ 1 prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant were permitted. Prior L or BCL2 family inhibitors, CNS involvement, and active hepatitis or HIV infection were not permitted. ANC > 1000/mm3, platelets > 75,000/mm3, creatinine clearance ≥50 ml/min, ALT/AST ≤ 3 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of L days 1-21 and V days 1-28 of a 28 day cycle (Table 1). O 1000 mg was administered on days 1, 8 and 15 of cycle 1 and then on day 1 of cycles 2-6. A 3+3 dose escalation schema was followed. DLTs included: treatment delays > 28 days; ANC < 500 / mm3 or platelets <25, 000 / mm3 persisting > 28 days; grade 4 febrile neutropenia or infection or grade 3 that fails to resolve within 7 days; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, tumor flare reaction controllable with steroids, tumor lysis syndrome that does not require dialysis, diarrhea, nausea, or vomiting responsive to medical treatment, transient electrolyte abnormalities or elevations of ALT / AST that resolve ≤ grade 1 within 48 hours, grade 3 infusion reactions responsive to medical therapy. Pts without significant toxicity or progression could continue treatment up to 12 cycles. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: 14 pts have been treated. Median age is 61 years (range 35-78 years) with 10 males. Median prior therapies is 2 (range 1-10). 5 pts had bulky disease (≥ 7.5 cm) and median baseline lactate dehydrogenase was 274 U/L (range 151-894, 12/14 above ULN 190 U/L). 10 pts were refractory to their last therapy. Histologies include DLBCL/transformed lymphoma (n=11) and FL (n=3). 3 pts were treated at dose level (DL) 1 (V 400 mg / L 15 mg). One pt experienced DLT, grade 3 neutropenic fever lasting > 7 days. DL 1 was expanded and no additional DLTs occurred. One pt with DLBCL was replaced for disease progression. 4 pts were then treated at DL 2 (V 600 mg / L 15 mg), and no DLTs were encountered. One pt was replaced due to missed doses of the oral agents. A total of 3 pts have been treated at DL 3 (V 800 mg / L 15 mg) and no DLTs have occurred at the time of data cutoff. Related grade 3-4 toxicities were primarily hematologic including neutropenia (n= 11, 78.6%), anemia (n=1, 7%), and thrombocytopenia (n=2, 14.3%). Grade 3-4 infections included sepsis, febrile neutropenia, pneumonia and a urinary tract infection. No clinically significant tumor lysis has occurred. Pts have received a median of 3 cycles (range 1-12) and 4 remain on therapy. Five pts have achieved a response. At DL 1, a pt with DLBCL, GC type, achieved a complete response (CR) and 2 pts with transformed FL achieved a partial response (PR). At DL 2, 1 pt with FL achieved a CR. At DL 3, 1 pt with transformed FL/double hit achieved a PR. Ten pts have discontinued, 6 with progression and 1 for DLT, alternative treatment, physician preference, and diagnosis of MDS in a patient with 3 prior lines of chemotherapy, respectively. Conclusions: Combined treatment with O, V, and L administered up to 12 cycles has been feasible with hematologic toxicity being the most common adverse event. Enrollment is ongoing and will include expansion cohorts in FL and DLBCL.Fowler et al. Activity of the immunologic doublet of lenalidomide plus obinutuzumab in relapsed follicular lymphoma: Results of a phase I/II study. JCO 2015; 35: 7531.Gerecitano et al. A Phase 1 Study of Venetoclax (ABT-199 / GDC-0199) Monotherapy in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma. Blood 2015; 126: 254.Zinzani et al. Phase 2 Study of Venetoclax Plus Rituximab or Randomized Ven Plus Bendamustine+Rituximab (BR) Versus BR in Patients with Relapsed/Refractory Follicular Lymphoma: Interim Data. Blood 2016; 128:617. Disclosures Maddocks: Merck: Research Funding; Pharmacyclics/Janssen: Honoraria; BMS: Research Funding; Pharmacyclics: Research Funding; Teva: Honoraria; Novartis: Research Funding; AstraZeneca: Honoraria. Jaglowski:Juno: Consultancy; Kite Pharma: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Blum:Celgene: Research Funding; Novartis: Research Funding; Morphosys: Research Funding; Seattle Genetics: Research Funding. Christian:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Immunomedics: Research Funding.

scholarly journals Interim Analysis of a Phase 1 Study of the Antibody-Drug Conjugate SGN-CD19A in Relapsed or Refractory B-Lineage Non-Hodgkin Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1741-1741 ◽  
Author(s):  
Craig H. Moskowitz ◽  
Andres Forero-Torres ◽  
Bijal D. Shah ◽  
Ranjana Advani ◽  
Paul Hamlin ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Phase 1 ◽  
Objective Response ◽  
Antibody Drug Conjugate ◽  
Employment Equity ◽  
Non Hodgkin Lymphoma ◽  
Equity Ownership ◽  
Grade 3

Abstract Background CD19, a B-cell specific marker, is expressed in the majority of patients with B-cell non-Hodgkin lymphoma (NHL). SGN-CD19A is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. Methods This ongoing phase 1, open-label, dose-escalation study investigates the safety, tolerability, pharmacokinetics, and antitumor activity of SGN-CD19A in patients with relapsed or refractory B-cell NHL (NCT 01786135). Eligible patients are ≥12 years of age and must have a confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL), including transformed follicular histology; mantle cell lymphoma (MCL); follicular lymphoma grade 3 (FL3); Burkitt lymphoma; or B-cell lymphoblastic lymphoma. Patients must be relapsed or refractory to at least 1 prior systemic regimen. Patients with DLBCL or FL3 must have also received intensive salvage therapy with or without autologous stem cell transplant (SCT), unless they refused or were deemed ineligible. A modified continual reassessment method is used for dose allocation and maximum tolerated dose (MTD) estimation. SGN-CD19A is administered IV on Day 1 of 21-day cycles (0.5–6 mg/kg). Response is assessed with CT and PET scans according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results To date, 44 patients have been treated: 39 patients (89%) with DLBCL (including 10 with transformed DLBCL), 4 (9%) with MCL, and 1 (2%) with FL3. Median age was 65 years (range, 33–81). Patients had a median of 2 prior systemic therapies (range, 1–7), and 10 patients (23%) had autologous SCT. Twenty-six patients (59%) were refractory to their most recent prior therapy, and 18 (41%) were relapsed. Patients received a median of 3 cycles of treatment (range, 1–12) at doses from 0.5–6 mg/kg. Eleven patients (25%) remain on treatment, and 33 have discontinued treatment (18 due to progressive disease [PD], 5 for investigator decision, 5 for adverse events [AE], 4 because of patient decision/non-AE, and 1 for SCT). No dose-limiting toxicity (DLT) in Cycle 1 has been reported. Treatment-emergent AEs reported in ≥20% of patients were blurred vision (59%), dry eye (39%), fatigue (39%), constipation (32%), keratopathy (23%), and pyrexia (20%). Corneal exam findings consistent with superficial microcystic keratopathy were observed in 25 patients (57%) and were mostly Grade 1/2. Grade 3/4 corneal AEs were observed in 4 patients at the higher doses; the majority resolved or improved to Grade 1/2 at last follow-up. Corneal AEs were treated with ophthalmic steroids, and during the trial steroid eye drop prophylaxis was instituted with each dose of study drug. SGN-CD19A ADC plasma exposures were approximately dose-proportional. Accumulation was observed following multiple dose administrations, consistent with a mean terminal half-life of about 2 weeks, suggesting less frequent dosing might be possible. In the 43 efficacy-evaluable patients, the objective response rate (ORR) is 30% (95% CI [17, 46]), including 7 complete responses (CRs; 16%) and 6 partial responses (PRs; 14%). Of the 13 patients with an objective response, 8 are still on study with follow-up times of 0.1–31 weeks; 2 are no longer on study; and 3 had subsequent PD or death with response durations of 14, 19, and 31 weeks. Table Best Clinical Response by Disease Status Relative to Most Recent Therapy, n (%) Relapsed N=17 Refractory N=26 Total N=43 CR 5 (29) 2 (8) 7 (16) PR 4 (24) 2 (8) 6(14) SD 4 (24) 9 (35) 13 (30) PD 4 (24) 13 (50) 17 (40) ORR (CR + PR), (95% CI) 53 (28, 77) 15 (4, 35) 30 (17, 46) Conclusions To date, SGN-CD19A has shown evidence of clinical activity with an ORR of 30% and CR rate of 16%. Enrollment in the trial is ongoing to further refine optimal dose and schedule. SGN-CD19A is generally well-tolerated. No DLTs have been observed in tested dose levels. Observed ocular AEs are manageable with steroid eye drops and dose modifications. The high response rate (53%) in relapsed patients and low rate of bone marrow suppression or neuropathy suggest that SGN-CD19A could be incorporated into novel combination regimens in earlier lines of therapy. Disclosures Moskowitz: Merck: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Off Label Use: SGN-CD19A is an investigational agent being studied in patients with B-cell malignancies. SGN-CD19A is not approved for use. . Forero-Torres:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Shah:Pharmacyclics: Speakers Bureau; SWOG: Consultancy; Celgene: Consultancy, Speakers Bureau; NCCN: Consultancy; Seattle Genetics, Inc.: Research Funding; Janssen: Speakers Bureau. Advani:Janssen Pharmaceuticals: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Takeda International Pharmaceuticals Co.: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other. Hamlin:Seattle Genetics, Inc.: Consultancy, Research Funding. Kim:Bayer: Consultancy; Eli Lily: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding. Kostic:Seattle Genetics, Inc.: Employment, Equity Ownership. Sandalic:Seattle Genetics, Inc.: Employment, Equity Ownership. Zhao:Seattle Genetics, Inc.: Employment, Equity Ownership. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding, Travel expenses Other.

VOICE trial: Final results from multicenter phaseII study of assessment of clinical efficiency and safety in capecitabine plus intermittent oxaliplatin together with bevacizumab as first-line therapy for patients with advanced colorectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 740-740 ◽  
Author(s):  
Chihiro Kosugi ◽  
Keiji Koda ◽  
Tadamichi Denda ◽  
Keiichiro Ishibashi ◽  
Hideyuki Ishida ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Peripheral Neuropathy ◽  
Primary Endpoint ◽  
Sensory Neuropathy ◽  
Severe Neutropenia ◽  
First Line ◽  
Peripheral Sensory Neuropathy ◽  
First Line Therapy ◽  
Line Therapy ◽  
Peripheral Sensory

740 Background: The FOLFOX with bevacizumab (B-mab) has been established as a standard first-line therapy for metastatic colorectal cancer (mCRC), and OPTIMOX1 study suggested that stop and go strategy for oxaliplatin reduced peripheral sensory neuropathy. The CapeOx is one of the standard treatments for mCRC that has been proven to be as effective as the FOLFOX regimen. Thus we accessed the efficacy and safety of the combination of intermittent CapeOx + B-mab as a first-line therapy in patients with mCRC in this trial. Methods: Eligibility criteria included ECOG PS: 0–1, No Peripheral neuropathy ( < Grade 1). Patients received CapeOX (oxaliplatin 130mg/m2, capecitabine 2000mg/m2 + B-mab 7.5mg/kg) q3 weeks for 5 cycles, maintenance without oxaliplatin for 5 cycles, and reintroduction CapeOX + B-mab for 5 cycles until progression. Primary endpoint was Progression Free Survival (PFS). Results: Between March 2011 and August 2013, 55 pts were enrolled. Baseline characteristics were median age of 67 years (range, 20–83); PS 0/1 (49/6 pts); male/female (33/22 pts), colon/rectum (28/27pts) and metastatic lesion liver/lung/lymph nodes (32/18/21 pts). A total of 47 pts were evaluated as Par Protocol Set population. 38 pts moved from initial CapeOX to maintenance Capecitabine. 20 pts moved to CapeOx reintroduction. Median PFS was 14.7months (95%CI, 8.6–19.5) and Median TTF was 12.3 months (95%CI, 10.3–14.3). Best overall response rate was 48.0%. Oxaliplatin reintroduction rate was 57.4%. Main grade 3/4 toxicity were: neutropenia (1 pt), anemia (1 pt), peripheral neuropathy (1 pt), allergic reaction of oxaliplatin (1 pt), deep vein thrombosis (1 pt), nausea (1 pt), hand-foot syndrome (1 pt), and hypertension (1 pt). Conclusions: This study met its primary endpoint PFS. CapeOx intermittent oxaliplatin indicated to reduce incidence of severe neutropenia and peripheral sensory neuropathy. The results suggested that our treatment strategy was well tolerate and effective for first line therapy in mCRC, and maintenance duration for 5 cycles, was reasonable. Clinical trial information: UMIN000005732.

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