Search

SUPPLEMENTARY METHODS

Purpose: To evaluate the safety, preliminary efficacy, and pharmacokinetics of inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, in combination with the immunochemotherapeutic regimen, rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma (NHL).Experimental Design: In part 1 (n = 16), patients received inotuzumab ozogamicin plus R-CVP on a 21-day cycle with escalating doses of cyclophosphamide first then inotuzumab ozogamicin. Part 2 (n = 10) confirmed the safety and tolerability of the maximum tolerated dose (MTD), which required a dose-limiting toxicity rate of n = 22) evaluated the preliminary efficacy of inotuzumab ozogamicin plus R-CVP.Results: The MTD was determined to be standard-dose R-CVP plus inotuzumab ozogamicin 0.8 mg/m2. The most common treatment-related grade ≥3 AEs in the MTD cohort (n = 38) were hematologic: neutropenia (74%), thrombocytopenia (50%), lymphopenia (42%), and leukopenia (47%). Among the 48 patients treated in the study, 13 discontinued due to AEs, most commonly thrombocytopenia (n = 10). Overall, 13 patients died, including one death due to treatment-related pneumonia secondary to neutropenia. Among patients receiving the MTD (n = 38), the overall response rate (ORR) was 84% (n = 32), including 24% (n = 9) with complete response; the ORR was 100% for patients with indolent lymphoma (n = 27) and 57% for those with aggressive histology lymphoma (n = 21).Conclusions: Inotuzumab ozogamicin at 0.8 mg/m2 plus full dose R-CVP was associated with manageable toxicities and demonstrated a high rate of response in patients with relapsed/refractory CD22+ B-cell NHL. The study is registered at ClinicalTrials.gov (NCT01055496). Clin Cancer Res; 22(19); 4807–16. ©2016 AACR.

Purpose:We assessed the relationship between cluster of differentiation-22 (CD22) expression and outcomes of inotuzumab ozogamicin versus standard of care (SC) in INO-VATE (NCT01564784).Patients and Methods:Adults with relapsed/refractory B-cell precursor CD22-positive (by local or central laboratory) acute lymphoblastic leukemia were randomized to inotuzumab ozogamicin (n = 164) or SC (n = 162). Outcomes were analyzed by baseline CD22 positivity (percentage of leukemic blasts CD22 positive, ≥90% vs. Results:Most patients had high (≥90%) CD22 positivity per central laboratory. The response rate was significantly higher with inotuzumab ozogamicin versus SC. Minimal/measurable residual disease negativity, duration of remission (DoR), progression-free survival, and overall survival (OS) were significantly better with inotuzumab ozogamicin versus SC in patients with CD22 positivity ≥90%. Fewer patients had CD22 positivity Conclusions:Inotuzumab ozogamicin demonstrated a favorable benefit–risk profile versus SC in patients with higher and lower CD22 expression. Patients with high CD22 expression and normal cytogenetics benefited the most from inotuzumab ozogamicin therapy.

Table S1. Dose Escalation of C (3 levels) or InO (2 levels) and Treatment Schedule Used to Determine the MTD Based on a Standard 3+3 Design; Table S2. AEs Leading to Permanent Discontinuation or Modification of the MTD

Supplementary Data

PARP inhibitor; Androgen receptor; Enzalutamide Inhibidor de PARP; Receptor d'andrògens; Enzalutamida Inhibidor de PARP; Receptor de andrógenos; Enzalutamida PARP inhibitors in combination with androgen receptor-targeted therapy have demonstrated potential in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Here, we describe the design and rationale of the multinational, phase III, two-part TALAPRO-2 study comparing talazoparib plus enzalutamide versus placebo plus enzalutamide as a first-line treatment for patients with mCRPC with or without DNA damage response (DDR) alterations. This study has two co-primary end points: radiographic progression-free survival (rPFS) by blinded independent clinical review in all-comers (cohort 1) and in patients with DDR alterations (cohort 2). TALAPRO-2 will demonstrate whether talazoparib plus enzalutamide can significantly improve the efficacy of enzalutamide in terms of rPFS in both molecularly unselected and DDR-deficient patients with mCRPC (NCT03395197).

What is this summary about? This summary describes the design of an ongoing research study (also known as a clinical trial) called TALAPRO-2. The TALAPRO-2 trial is testing the combination of two medicines called talazoparib and enzalutamide as a first treatment in adult men with metastatic castration-resistant prostate cancer. The study began in December 2017 and has enrolled 1037 adult men with metastatic castration-resistant prostate cancer from 26 countries. What is metastatic castration-resistant prostate cancer? Metastatic castration-resistant prostate cancer is a type of cancer that has advanced beyond the prostate and continues to grow even when testosterone levels in the blood are suppressed. Which medicines are being tested? The combination of talazoparib plus enzalutamide will be compared with enzalutamide plus placebo. Enzalutamide is approved to treat men with prostate cancer. Talazoparib is not approved to treat men with prostate cancer. A placebo does not contain any active ingredients and is also known as a sugar pill. What are the aims of the TALAPRO-2 trial? The TALAPRO-2 trial will find out if combining talazoparib with enzalutamide increases the length of time the men in the study live without their cancer getting worse compared with enzalutamide plus placebo. The study will also measure how long men in the study live and any side effects the men have while they are taking the study medicines. Researchers are also testing the DNA from the tumor cells of all men in the study to find out if they have faulty DNA repair genes. Clinical Trial Registration: NCT0339519 ( ClinicalTrials.gov )

Inotuzumab ozogamicin (InO) is a targeted treatment for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). InO was previously studied in INO-VATE, an international, open-label, randomized phase 3 trial comparing InO against standard of care (SoC). In the present subgroup analysis, we evaluated outcomes in the 55 Asian patients who were randomized in INO-VATE (31 InO and 24 SoC). Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 22/31 patients treated with InO versus 5/24 treated with SoC. In the InO arm, more of the patients achieving CR/CRi were minimal residual disease (MRD)-negative (17/22 versus 1/5), and more patients proceeded directly to hematopoietic stem cell transplantation (15/31 versus 3/24). Median overall survival for the respective arms was 5.8 versus 3.9 months (hazard ratio 0.67; 97.5% CI 0.28, 1.62). In the safety analysis (n = 51), the most common adverse events were hematologic. Sinusoidal obstruction syndrome was reported in five InO patients and one SoC patient. In conclusion, Asian patients with relapsed or refractory B-cell ALL experienced improved efficacy with InO versus SoC, with an efficacy and safety profile consistent with results of the overall INO-VATE population. Clinical trial registration: ClinicalTrials.gov identifier: NCT01564784.

Purpose: We assessed the relationship between cluster of differentiation-22 (CD22) expression and outcomes of inotuzumab ozogamicin versus standard of care (SC) in INO-VATE (NCT01564784). Patients and Methods: Adults with relapsed/refractory B-cell precursor CD22-positive (by local or central laboratory) acute lymphoblastic leukemia were randomized to inotuzumab ozogamicin (n = 164) or SC (n = 162). Outcomes were analyzed by baseline CD22 positivity (percentage of leukemic blasts CD22 positive, ≥90% vs. Results: Most patients had high (≥90%) CD22 positivity per central laboratory. The response rate was significantly higher with inotuzumab ozogamicin versus SC. Minimal/measurable residual disease negativity, duration of remission (DoR), progression-free survival, and overall survival (OS) were significantly better with inotuzumab ozogamicin versus SC in patients with CD22 positivity ≥90%. Fewer patients had CD22 positivity Conclusions: Inotuzumab ozogamicin demonstrated a favorable benefit–risk profile versus SC in patients with higher and lower CD22 expression. Patients with high CD22 expression and normal cytogenetics benefited the most from inotuzumab ozogamicin therapy.

Karyotype is frequently used to predict response and outcome in leukemia. This post hoc exploratory analysis evaluated the relationship between baseline cytogenetics and outcome in patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) treated with inotuzumab ozogamicin (InO), a humanized CD22 antibody conjugated to calicheamicin, in the phase 3, open-label, randomized INO-VATE trial. Data as of March 8, 2016, are presented in this analysis. Of the 326 patients randomized, 284 had screening karyotyping data (144 in the InO arm and 140 in the standard care [SC] arm). With InO, complete remission or complete remission with incomplete hematologic recovery (CR/CRi), minimal residual disease negativity rates, and overall survival (OS) were not significantly different between cytogenetic subgroups. CR/CRi rates favored InO over SC in the diploid with ≥20 metaphases, complex, and "other" cytogenetic subgroups. The OS hazard ratio favored InO over SC in the diploid with ≥20 metaphases, complex, and other cytogenetic subgroups. Generally, InO is effective and provides substantial clinical benefit in patients with R/R ALL who have specific baseline karyotypes.

BACKGROUND Inotuzumab ozogamicin (InO) has demonstrated efficacy and tolerability in patients aged 18 to 78 years with relapsed/refractory acute lymphoblastic leukemia (ALL) in the INO-VATE trial. This subset analysis compared the efficacy and safety of InO in younger and older patients. METHODS Intent-to-treat analyses of morphologic responses and overall survival (OS) included 326 randomized patients, and safety assessments included 307 patients receiving 1 or more doses of the study treatment. Of the 326 patients, 164 received InO at a starting dose of 1.8 mg/m2 /cycle (0.8 mg/m2 on day 1 and 0.5 mg/m2 on days 8 and 15 of a 21- to 28-day cycle [≤6 cycles]); 60 patients were aged ≥55 years, and 104 were aged

TPS5089 Background: TALA blocks poly(ADP-ribose) polymerase (PARP) activity and traps PARP on single-strand DNA breaks, preventing DNA damage repair (DDR) and causing death of cells with DDR alterations (eg, BRCA1/2).a TALA is approved in multiple countries as monotherapy for germline BRCA1/2-mutated human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Olaparib and rucaparib are PARP inhibitors approved for use in mCRPC. ENZA is an androgen receptor (AR) inhibitor and an established therapy for mCRPC. As PARP activity has been shown to support AR function, inhibition of PARP is expected to increase sensitivity to AR-directed therapies. In addition, AR blockade downregulates homologous recombination repair gene transcription, which induces a “ BRCAness” phenotype. A proof-of-concept study combining olaparib and abiraterone (abi) in pts with mCRPC demonstrated improved median radiographic progression-free survival (rPFS) vs placebo plus abi (13.8 vs 8.2 months) and a tolerable safety profile. Therefore, ENZA may be efficacious regardless of DDR alterations. TALAPRO-2 (NCT03395197) is a Phase 3, 2-part study evaluating the efficacy, safety, pharmacokinetics, and patient-reported outcomes (PROs) of TALA plus ENZA in pts with mCRPC with or without DDR alterations. Methods: Enrollment goal is 1037 patients (pts; 19 pts, part 1 dose-finding [completed]; 1018 pts, part 2 placebo-controlled [ongoing; accrual completed in unselected cohort]). Key eligibility criteria: age ≥18 years; asymptomatic/mildly symptomatic mCRPC; ECOG performance status ≤1; metastatic disease (no brain metastases); and no prior life-prolonging systemic therapy for nonmetastatic CRPC or mCRPC. Prior therapies (excluding novel AR inhibitors) in the castration-sensitive (CSPC) setting are allowed. ADT must continue throughout the study. The randomized double-blind portion (part 2) will evaluate safety, efficacy, and PROs of TALA (0.5 mg once daily [QD]) + ENZA (160 mg QD) vs placebo + ENZA (160 mg QD). Pts are stratified by prior novel hormonal therapy or docetaxel for CSPC or mCSPC (yes or no) and DDR alteration status (deficient vs nondeficient/unknown). The primary endpoint is rPFS, defined as time to progression in soft tissue per RECIST v.1.1 or in bone per PCWG3 criteria by independent central review or death. The key secondary endpoint is overall survival. Efficacy is assessed radiographically every 8 weeks up to Week 25 and every 8–12 weeks thereafter. rPFS will be compared between the two arms by a one-sided stratified log-rank test. Pt recruitment is ongoing at 223 sites in 26 countries, including 32 states across the US, and Europe, Israel, South America, South Africa, and Asia-Pacific region. aDDR alterations are defined as known/likely pathogenic variants or homozygous deletions. Clinical trial information: NCT03395197.

Purpose: To evaluate the safety, preliminary efficacy, and pharmacokinetics of inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, in combination with the immunochemotherapeutic regimen, rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma (NHL). Experimental Design: In part 1 (n = 16), patients received inotuzumab ozogamicin plus R-CVP on a 21-day cycle with escalating doses of cyclophosphamide first then inotuzumab ozogamicin. Part 2 (n = 10) confirmed the safety and tolerability of the maximum tolerated dose (MTD), which required a dose-limiting toxicity rate of Results: The MTD was determined to be standard-dose R-CVP plus inotuzumab ozogamicin 0.8 mg/m2. The most common treatment-related grade ≥3 AEs in the MTD cohort (n = 38) were hematologic: neutropenia (74%), thrombocytopenia (50%), lymphopenia (42%), and leukopenia (47%). Among the 48 patients treated in the study, 13 discontinued due to AEs, most commonly thrombocytopenia (n = 10). Overall, 13 patients died, including one death due to treatment-related pneumonia secondary to neutropenia. Among patients receiving the MTD (n = 38), the overall response rate (ORR) was 84% (n = 32), including 24% (n = 9) with complete response; the ORR was 100% for patients with indolent lymphoma (n = 27) and 57% for those with aggressive histology lymphoma (n = 21). Conclusions: Inotuzumab ozogamicin at 0.8 mg/m2 plus full dose R-CVP was associated with manageable toxicities and demonstrated a high rate of response in patients with relapsed/refractory CD22+ B-cell NHL. The study is registered at ClinicalTrials.gov (NCT01055496). Clin Cancer Res; 22(19); 4807–16. ©2016 AACR.

The prognosis for adults with relapsed acute lymphoblastic leukemia is poor. We sought to determine whether inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, results in better outcomes in patients with relapsed or refractory acute lymphoblastic leukemia than does standard therapy.In this phase 3 trial, we randomly assigned adults with relapsed or refractory acute lymphoblastic leukemia to receive either inotuzumab ozogamicin (inotuzumab ozogamicin group) or standard intensive chemotherapy (standard-therapy group). The primary end points were complete remission (including complete remission with incomplete hematologic recovery) and overall survival.Of the 326 patients who underwent randomization, the first 218 (109 in each group) were included in the primary intention-to-treat analysis of complete remission. The rate of complete remission was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group (80.7% [95% confidence interval {CI}, 72.1 to 87.7] vs. 29.4% [95% CI, 21.0 to 38.8], P0.001). Among the patients who had complete remission, a higher percentage in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease (0.01% marrow blasts) (78.4% vs. 28.1%, P0.001); the duration of remission was longer in the inotuzumab ozogamicin group (median, 4.6 months [95% CI, 3.9 to 5.4] vs. 3.1 months [95% CI, 1.4 to 4.9]; hazard ratio, 0.55 [95% CI, 0.31 to 0.96]; P=0.03). In the survival analysis, which included all 326 patients, progression-free survival was significantly longer in the inotuzumab ozogamicin group (median, 5.0 months [95% CI, 3.7 to 5.6] vs. 1.8 months [95% CI, 1.5 to 2.2]; hazard ratio, 0.45 [97.5% CI, 0.34 to 0.61]; P0.001); the median overall survival was 7.7 months (95% CI, 6.0 to 9.2) versus 6.7 months (95% CI, 4.9 to 8.3), and the hazard ratio was 0.77 (97.5% CI, 0.58 to 1.03) (P=0.04). In the safety population, the most frequent grade 3 or higher nonhematologic adverse events with inotuzumab ozogamicin were liver-related. Veno-occlusive liver disease of any grade occurred in 15 patients (11%) who received inotuzumab ozogamicin and in 1 patient (1%) who received standard therapy.The rate of complete remission was higher with inotuzumab ozogamicin than with standard therapy, and a higher percentage of patients in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease. Both progression-free and overall survival were longer with inotuzumab ozogamicin. Veno-occlusive liver disease was a major adverse event associated with inotuzumab ozogamicin. (Funded by Pfizer; INO-VATE ALL ClinicalTrials.gov number, NCT01564784.).

5566 Background: PARP inhibitors (PARPi) show antitumor activity in mCRPC/DDRm pts treated with novel hormonal therapy (NHT). TALAPRO-1 is an open-label study evaluating TALA (potent PARP inhibitor/trapper) in men with mCRPC/DDRm. We report a planned IA (Dec 2019). Methods: TALAPRO-1 (NCT03148795) is enrolling pts (N ≈ 100) with measurable soft tissue disease, progressive mCRPC, and DDRm likely to sensitize to PARPi ( ATM, ATR, BRCA1/2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received 1–2 chemotherapy regimens (≥1 taxane-based) for metastatic disease and progressed on ≥1 NHT (enzalutamide/abiraterone acetate) given for mCRPC. DDRm are defined as known/likely pathogenic variants or homozygous deletions. Pts receive oral TALA 1 mg/day (moderate renal impairment 0.75 mg/day) until radiographic progression, unacceptable toxicity, consent withdrawal or death. Primary endpoint is objective response rate (ORR). Secondary endpoints: time to OR; response duration; PSA decrease ≥50%; circulating tumor cell (CTC) count conversion (to CTC = 0 and

Inotuzumab ozogamicin (InO) has demonstrated efficacy and tolerability in patients aged 18 to 78 years with relapsed/refractory acute lymphoblastic leukemia (ALL) in the INO-VATE trial. This subset analysis compared the efficacy and safety of InO in younger and older patients.Intent-to-treat analyses of morphologic responses and overall survival (OS) included 326 randomized patients, and safety assessments included 307 patients receiving 1 or more doses of the study treatment. Of the 326 patients, 164 received InO at a starting dose of 1.8 mg/mFor older and younger patients, the median duration of InO therapy and the types and frequencies of adverse events of any grade were generally similar. Although the remission rates, median duration of remission (DOR), and progression-free survival were similar with InO for those aged55 years and those aged ≥55 years, OS was longer for younger patients (median, 8.6 vs 5.6 months; hazard ratio, 0.610). Among patients proceeding to hematopoietic stem cell transplantation after InO treatment (28% of older patients and 58% of younger patients), the incidence of veno-occlusive disease was greater in older patients (41% vs 17%). The study database was not locked at the time of this analysis.InO was tolerable in older patients with relapsed/refractory ALL. Although OS was longer for younger patients versus older patients, InO demonstrated high response rates with similar DOR in the 2 age groups. Cancer 2018;124:1722-32. © 2018 American Cancer Society.

119 Background: Phase 2 and 3 studies with poly(ADP-ribose) polymerase inhibitors (PARPi) have demonstrated antitumor activity in patients (pts) with mCRPC with DDRmut who were previously treated with novel hormonal therapy (NHT). We report the first IA of a Phase 2 study of TALA, a potent inhibitor and trapper of PARP. Methods: TALAPRO-1 (NCT03148795) is enrolling pts (N ≈ 100) with measurable soft tissue disease, progressive mCRPC, and DDRmut likely to sensitize to PARPi (including ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received 1–2 chemotherapy regimens (≥1 taxane-based) and progressed on ≥1 NHT (enzalutamide/abiraterone acetate). Pts receive oral TALA 1 mg/d (moderate renal impairment, 0.75 mg/d) until radiographic progression, unacceptable toxicity, or consent withdrawal. Primary endpoint is objective response rate (ORR; blinded independent review). Secondary endpoints are time to OR, duration of response, prostate-specific antigen (PSA) decrease ≥50%, circulating tumor cell (CTC) count conversion (to CTC = 0 and BRCA1/2 50.0% (27.2–72.8), ORRATM 7.1% (0.2–33.9). Overall median (95% CI) rPFS was 5.6 months (mo) (3.5–8.2), rPFSBRCA1/2 8.2 mo (5.6–NE), rPFSATM 3.5 mo (1.7–8.1). Most common treatment-emergent adverse events (≥20%) were anemia, nausea, asthenia, decreased appetite, constipation, and platelet count decreased. Conclusions: TALA monotherapy demonstrates encouraging antitumor activity in docetaxel-pretreated mCRPC pts, especially those with BRCA1/2mut, and was generally well tolerated. This study was sponsored by Pfizer Inc. Clinical trial information: NCT03148795.

Introduction: Inotuzumab ozogamicin (InO) is a CD22-directed antibody-calicheamicin conjugate. Patients (pts) with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL) treated with InO vs standard of care chemotherapy (SC) had significantly better response, and improved survival in INO-VATE (NCT01564784). Based on central laboratory assessment, this favorable benefit-risk profile of InO was independent of leukemic blast CD22 positivity (≥90% vs Methods: Adult pts (≥18 yrs) with R/R CD22-positive (based on local or central lab results) ALL in salvage 1 or 2 were randomized to InO (n=164) or SC (n=162) (details: NEJM 2016;375:740-53). InO starting dose was 1.8 mg/m2/cycle (0.8 mg/m2 on Day 1; 0.5 mg/m2 on Days 8 & 15 of a 21-28-day cycle for ≤6 cycles) and reduced to 1.5 mg/m2/cycle for pts with complete remission (CR) or CR with incomplete hematologic recovery (CRi). SC included fludarabine/cytarabine [Ara-C]/granulocyte colony-stimulating factor, Ara-C plus mitoxantrone, or high-dose Ara-C. CD22 positivity (% of leukemic blasts expressing CD22) was measured at screening by flow cytometry or immunohistochemistry. Efficacy (CR/CRi, minimal residual disease [MRD, assessed in central labs] among responders, overall survival [OS], progression-free survival [PFS], and duration of remission [DoR]) and safety outcomes were analyzed by CD22 positivity quartiles, Quartile 1 (Q1) having the lowest and Q4 the highest CD22 positivity. Data cutoff: 04Jan2017. P-values are 1-sided. Results: Baseline CD22 positivity per local lab was available for 152 pts per arm. CD22 positivity (%) was comparable between treatment arms for each quartile; median (range) was 21.9 (1.0-39.4) for InO vs 23.9 (0.0-39.0) for SC in Q1, 55.5 (40.0-68.9) vs 56.3 (40.0-66.0) in Q2, 84.0 (70.0-92.0) vs 84.0 (70.0-92.9) in Q3, and 98.0 (93.0-100.0) for both arms in Q4. CR/CRi rates showed no difference among quartiles in the InO (P=0.5906) or SC arm (P=0.2061), and were significantly higher with InO vs SC for all quartiles (Q1: 81.6% vs 41.2%, P=0.0002; Q2: 68.4% vs 36.8%, P=0.0029; Q3: 73.2% vs 27.0%, P Cytopenias were the most common ≥grade 3 adverse events in the InO arm, with similar rates across the quartiles (Q1-Q4: neutropenia: 52.6%, 47.4%, 39.0%, and 48.6%; thrombocytopenia: 34.2%, 44.7%, 46.3%, and 31.4%; febrile neutropenia: 15.8%, 28.9%, 29.3%, and 34.3%). Rates of ≥grade 3 infections were 21.1%, 26.3%, 36.6%, and 31.4% for Q1-Q4. In InO-treated pts, rates of ≥grade 3 hyperbilirubinemia were similar for the lower quartiles (Q1-Q3: 5.3%, 7.9%, and 2.4%; 11.4% for Q4); rates of ≥grade 3 veno-occlusive liver disease (VOD)/sinusoidal obstruction syndrome (SOS) within 2 years of randomization regardless of causality were 13.2%, 7.9%, 7.3%, and 17.1% in Q1-Q4, respectively; 3 grade 5 VOD/SOS events occurred in Q1, 2 in Q4, and 0 in Q2 and Q3. Conclusions: In general, the results showed improvement in measures of efficacy for InO over SC that was comparable across all 4 CD22 positivity quartiles per local lab assessments. For DoR, PFS, and OS, there was a suggestion of greater benefit for pts in higher CD22 positivity quartiles treated with InO, though these analyses are limited by the small sample size. These trends are in alignment with those previously presented for central lab CD22 positivity and receptor density (Blood 2017;130[Suppl 1]:1272). Overall, InO demonstrated a favorable benefit/risk profile for pts with R/R B cell precursor ALL independent of local lab CD22 positivity. Disclosures Kantarjian: Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Novartis: Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding; BMS: Research Funding; Immunogen: Research Funding. Stock:Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees. Cassaday:Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests. DeAngelo:Celgene: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Takeda Pharmaceuticals: Consultancy; Abbvie: Research Funding; Shire: Consultancy; Amgen: Consultancy; GlycoMimetics: Research Funding; Incyte: Consultancy; Novartis: Consultancy, Research Funding; Blueprint: Consultancy, Research Funding; Pfizer: Consultancy. Jabbour:Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding. O'Brien:Sunesis: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Eisai: Consultancy; Acerta: Research Funding; TG Therapeutics: Consultancy, Research Funding; Alexion: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Aptose Biosciences, Inc: Consultancy; GlaxoSmithKline: Consultancy; Astellas: Consultancy; Kite: Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Amgen: Consultancy; Regeneron: Research Funding; Verastem: Consultancy; Vaniam Group LLC: Consultancy; Celgene: Consultancy. Stelljes:Novartis: Honoraria; MDS: Consultancy; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding. Wang:Pfizer: Employment, Equity Ownership. Paccagnella:Pfizer: Employment, Equity Ownership. Nguyen:Navigate BioPharma Services, Inc., a Novartis Subsidiary: Employment; Novartis: Equity Ownership. Sleight:Pfizer: Employment, Equity Ownership. Vandendries:Pfizer: Employment, Equity Ownership. Neuhof:Pfizer: Employment, Equity Ownership. Laird:Pfizer: Employment, Equity Ownership. Advani:Amgen: Research Funding; Abbvie: Research Funding; Macrogenics: Research Funding; Pfizer: Honoraria, Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy.

Objective: To evaluate safety, tolerability, and preliminary activity of inotuzumab ozogamicin (InO) plus rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma (NHL). Methods: Patients received InO plus R-GDP (21-day cycle; six-cycle maximum) using up-and-down dose-escalation schema for gemcitabine and cisplatin to define the highest dosage regimen(s) with acceptable toxicity (Part 1; n = 27). Part 2 (n = 10) confirmed safety and tolerability; Part 3 (n = 18) evaluated preliminary efficacy. Results: Among 55 patients enrolled, 42% were refractory at baseline (median 2 [range, 1–6] prior therapies); 38% had diffuse large B-cell lymphoma (DLBCL). The highest dosage regimen with acceptable toxicity was InO 0.8 mg/m2, rituximab 375 mg/m2, cisplatin 50 mg/m2, gemcitabine 500 mg/m2 (day 1 only) and dexamethasone 40 mg (days 1–4); this was confirmed in Part 2, in which three patients had dose-limiting toxicities (grade 4 thrombocytopenia [n = 2], febrile neutropenia [n = 2]). Most frequent treatment-related adverse events were thrombocytopenia (any grade, 85%; grade ≥3, 75%) and neutropenia (69%; 62%). Overall (objective) response rate (ORR) was 53% (11 complete, 18 partial responses); ORR was 71%, 33%, and 62% in patients with follicular lymphoma (n = 14), DLBCL (n = 21), and mantle cell lymphoma (n = 13), respectively. Conclusions: InO 0.8 mg/m2 plus R-GDP was associated with manageable toxicity, although gemcitabine and cisplatin doses were lower than in the standard R-GDP regimen due to hematologic toxicity. Evidence of antitumor activity was observed; however, these exploratory data should be interpreted with caution due to the small sample size and short follow-up duration (Clinicaltrials.gov number: NCT01055496).

Purpose Patients with Ewing sarcoma (ES) with metastases and those who relapse fare poorly and receive therapies that carry significant toxicity. This phase 1/2 study was conducted to evaluate the efficacy of figitumumab in advanced ES. Patients and Methods Patients with sarcoma 10 to 18 years old were enrolled in two dose escalation cohorts (20 and 30 mg/Kg intravenously every 4 weeks) in the phase 1 portion of the study. Patients with ES 10 years old or older were enrolled in the phase 2 portion of the study. The primary phase 2 objective was objective response rate (ORR). Results Thirty-one patients with ES (n = 16), osteosarcoma (n = 11), or other sarcomas (n = 4) were enrolled in the phase 1 portion of the study. Dose escalation proceeded to 30 mg/kg every 4 weeks with no dose-limiting toxicity identified. In the phase 2 portion of the study, 107 patients with ES received figitumumab at 30 mg/kg every 4 weeks for a median of 2 cycles (range, 1 to 16). Sixty three percent of phase 2 patients had received at least three prior treatment regimens. Of 106 evaluable patients, 15 had a partial response (ORR, 14.2%) and 25 had stable disease. Median overall survival was 8.9 months. Importantly, patients with a pretreatment circulating free insulin-like growth factor (IGF) -1 lower than 0.65 ng/mL (n = 14) had a median OS of 3.6 months, whereas those with a baseline free IGF-1 ≥ 0.65 ng/mL (n = 84) had a median OS of 10.4 months (P < .001). Conclusion Figitumumab had modest activity as single agent in advanced ES. A strong association between pretreatment serum IGF-1 and survival benefit was identified.

Progress has been made towards the development of agents targeting tyrosine kinase receptors and other molecules involved in signalling pathways important for cell proliferation, motility, and apoptosis. Inhibitor molecules designed to be highly specific with the aim of decreasing toxicity have proven to be generally well tolerated. However, the efficacy of targeted agents may be impacted by cross-talk between pathways and downregulation of negative feed-back loops. That is the case of the IGF-IR/PI3K/Akt/mTOR pathway. This issue raises the question of how these targeted agents could be combined to prevent or delay resistance without significantly increasing toxicity. Several mTOR inhibitors have been approved for cancer therapy, and late-stage clinical trials of IGF-IR inhibitors are underway. The outcome of ongoing clinical studies of IGF-IR, PI3K, Akt and mTOR inhibitors as well as further testing of the combination of these agents will be key for the development of therapeutic options in a wide range of oncology indications.

Summary Background Figitumumab is a fully human IgG2 monoclonal antibody targeting the insulin-like growth-factor-1 receptor (IGF-1R). Preclinical data suggest a dependence on insulin-like growth-factor signalling for sarcoma subtypes, including Ewing's sarcoma, and early reports show antitumour activity of IGF-1R-targeting drugs in these diseases. Methods Between January, 2006, and August, 2008, patients with refractory, advanced sarcomas received figitumumab (20 mg/kg) in two single-stage expansion cohorts within a solid-tumour phase 1 trial. The first cohort (n=15) included patients with multiple sarcoma subtypes, age 18 years or older, and the second cohort (n=14) consisted of patients with refractory Ewing's sarcoma, age 9 years or older. The primary endpoint was to assess the safety and tolerability of figitumumab. Secondary endpoints included pharmacokinetic profiling and preliminary antitumour activity (best response by Response Evaluation Criteria in Solid Tumours [RECIST]) in evaluable patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, number NCT00474760. Findings 29 patients, 16 of whom had Ewing's sarcoma, were enrolled and received a total of 177 cycles of treatment (median 2, mean 6·1, range 1–24). Grade 3 deep venous thrombosis, grade 3 back pain, and grade 3 vomiting were each noted once in individual patients; one patient had grade 3 increases in aspartate aminotransferase and gammaglutamyltransferase concentrations. This patient also had grade 4 increases in alanine aminotransferase concentrations. The only other grade 4 adverse event was raised concentrations of uric acid, noted in one patient. Pharmacokinetics were comparable between patients with sarcoma and those with other solid tumours. 28 patients were assessed for response; two patients, both with Ewing's sarcoma, had objective responses (one complete response and one partial response) and eight patients had disease stabilisation (six with Ewing's sarcoma, one with synovial sarcoma, and one with fibrosarcoma) lasting 4 months or longer. Interpretation Figitumumab is well tolerated and has antitumour activity in Ewing's sarcoma, warranting further investigation in this disease. Funding Pfizer Global Research and Development.

Insulin-like growth factor 1 receptor signaling through upregulation of the stimulatory ligand IGF-II has been implicated in the pathogenesis of adrenocortical carcinoma. As there is a paucity of effective therapies, this dose expansion cohort of a phase 1 study was undertaken to determine the safety, tolerability, pharmacokinetics, and effects on endocrine markers of figitumumab in patients with adrenocortical carcinoma.Figitumumab was administered on day 1 of each 21-day cycle at the maximal feasible dose (20 mg/kg) to a cohort of patients with metastatic, refractory adrenocortical carcinoma. Serum glucose, insulin, and growth hormone were measured pre-study, at cycle 4 and study end. Pharmacokinetic evaluation was performed during cycles 1 and 4.Fourteen patients with adrenocortical carcinoma received 50 cycles of figitumumab at the 20 mg/kg. Treatment-related toxicities were generally mild and included hyperglycemia, nausea, fatigue, and anorexia. Single episodes of grade 4 hyperuricemia, proteinuria, and elevated gamma-glutamyltransferase were observed. Pharmacokinetics of figitumumab was comparable to patients with solid tumors other than adrenocortical carcinoma. Treatment with figitumumab increased serum insulin and growth hormone levels. Eight of 14 patients (57%) had stable disease.The side effect profile and pharmacokinetics of figitumumab were similar in patients with adrenocortical carcinoma in comparison to patients with other solid tumors. While hyperglycemia was the most common adverse event, no clear patterns predicting severity were observed. The majority of patients receiving protocol therapy with single agent figitumumab experienced stability of disease, warranting further evaluation.

Background: Inotuzumab ozogamicin (InO), a humanized anti-CD22 antibody-calicheamicin conjugate, produced a superior response compared with standard of care (SOC) for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) in an intent-to-treat (ITT) analysis of the first 218 of 326 patients (pts) randomized (ITT218) in the INO-VATE trial (complete remission [CR], including CR with incomplete hematologic recovery [CRi], 80.7% [95% CI, 72-88] vs 29.4% [21-39]; 1-sided P Methods: In the INO-VATE trial (NCT01564784), adults with CD22-positive ALL due to receive S1 or S2 treatment were randomized (1:1) to InO (starting dose 1.8 mg/m2/cycle [0.8 mg/m2 on day 1; 0.5 mg/m2 on days 8 and 15 of a 21-28 day cycle for ≤6 cycles]) or SOC (either fludarabine/cytarabine [ara-C]/granulocyte colony-stimulating factor [FLAG], ara-C plus mitoxantrone, or high-dose ara-C). Outcomes included investigator assessed CR/CRi, minimal residual disease (MRD)-negativity in responders (assessed by central flow cytometry [threshold Results: Baseline characteristics for the ITT326 were balanced for S1 vs S2 for InO (S1, n=108; S2, n=56) and SOC (S1, n=107; S2, n=55); except more S2 vs S1 pts were Philadelphia chromosome-positive (InO, 20% vs 10%; SOC, 24% vs 14%), had complex cytogenetics (InO, 30% vs 9%; SOC, 18% vs 11%), and had prestudy SCT (InO, 31% vs 11%; SOC, 28% vs 14%). For InO vs SOC, CR/CRi rates were significantly higher for both S1 and S2 pts (both 1-sided P≤0.0002; Table). For S1 vs S2, CR/CRi rates were numerically higher for the InO arm and were similar for the SOC arm; comparable MRD-negativity rates among responders were reported for the InO and SOC arm. None of these S1 vs S2 differences were significant. For S1 vs S2, DoR was longer for the InO and SOC arms; this difference was significant for the SOC arm. For InO vs SOC, PFS was significantly longer for both S1 and S2 pts. For this same comparison, OS was significantly longer for S1, but not S2. For S1 vs S2, PFS was numerically longer in both the InO and SOC arms; this difference was significant in the SOC arm. For S1 vs S2, OS was also numerically longer in the InO arm and was similar in the SOC arm. The most common Grade (Gr) ≥3 adverse events (AEs) in both S1 and S2 pts receiving InO or SOC were cytopenias; Gr ≥3 febrile neutropenia rates were similar for S1 vs S2 for the InO(24% vs 29%) and SOC (56% vs 51%) arms, as were Gr ≥3 infection rates (system-organ class: InO, 28% vs 28%; SOC; 54% vs 57%). For S2 vs S1,Gr ≥3 hepatobiliary AEs rates were higher for the InO (26% vs 12%) arm and were similar for the SOC (9% vs 6%) arm. During InO therapy or during follow-up without intervening SCT, more S2 vs S1 pts had veno-occlusive disease (VOD: 6% [n=3/51] vs 2% [n=2/111]).For InO vs SOC, poststudy SCT rates were significantly higher in both S1 and S2 pts (S1, 51% [56/111] vs 25% [24/95]; S2, 39% [20/51] vs 17% [8/47]; both P≤0.02); VOD rates in pts with poststudy SCT were higher for InO vs SOC (S1, 18% [10/56] vs 4% [1/24]; S2, 35% [7/20] vs 0% [0/8]). More S1 vs S2 pts receiving InO had poststudy SCT (51% [n=56/111] vs 39% [n=20/51]); the VOD rate among pts who receivedpoststudy SCT was greater for S2 (35% [n=7/20]) vs S1 (18% [n=10/56]). Seven of the VOD cases occurring in the InO arm were reversible.Five pts receiving InO had grade 5 VOD (all post-SCT). Conclusions: InO provides clinical benefit regardless of salvage status for pts with R/R ALL, while OS benefit appeared more evident in S1 pts. However, small sample sizes impose limits on interpretation of these results. InO safety profiles were similar across subgroups, except for the incidence of liver-toxicities, including VOD, which may be greater in heavily pretreated pts such as those in later lines of therapy. Disclosures Advani: Blinatumomab: Research Funding; Pfizer Inc.: Consultancy, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Stelljes:Pfizer: Consultancy. DeAngelo:Amgen: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Ariad: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Baxter: Consultancy. Liedtke:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stock:Gilead Sciences: Honoraria; Royalties for a chapter in Up to Date: Patents & Royalties; Sigma-Tau: Honoraria, Research Funding; Amgen: Honoraria; ADC Therapeutics: Honoraria. Gökbuget:Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. O'Brien:Celgene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Gilead Sciences: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Honoraria, Other: Travel, Accommodations, Expenses; Pfizer: Honoraria; Pharmacyclics: Honoraria; ProNAi: Honoraria; Regeneron: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy; CLL Global Research Foundation: Consultancy; Acerta Pharma: Research Funding. Wang:Pfizer: Employment, Equity Ownership. Wang:Pfizer: Employment, Equity Ownership. Paccagnella:Pfizer: Employment. Sleight:Pfizer: Employment, Equity Ownership. Vandendries:Pfizer Inc.: Employment, Equity Ownership.

7028Background: InO, an anti-CD22 antibody-calicheamicin conjugate, showed superior response vs standard care for R/R ALL in the phase III INO-VATE trial. Herein, effects of prior therapy on respon...

7029Background: InO, an anti-CD22 antibody-calicheamicin conjugate, has demonstrated superior response vs standard care for R/R ALL in the phase 3 INO-VATE trial (complete remission [CR]/CR with incomplete hematologic recovery [CRi], 81% [95% CI; 72–88]; minimal residual disease [MRD] negativity in responders, 78% [68–87]; median remission duration [DoR], 4.6 [3.9–5.4] mo). Herein, the efficacy and safety of InO in patients (pts) aged ≥55 vs

PurposeA phase I first-in-human study was conducted to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of the anti–insulinlike growth factor 1 receptor (IGF-IR) monoclonal antibody CP-751,871.Patients and MethodsAfter informed consent and screening, 47 patients with multiple myeloma in relapse or refractory phase were enrolled into 11 dose-escalation cohorts of CP-751,871 at doses from 0.025 to 20 mg/kg for 4 weeks. Patients with less than a partial response to CP-751,871 treatment were eligible to receive CP-751,871 in combination with oral dexamethasone at the discretion of the investigator. Treatment with CP-751,871 and rapamycin with or without dexamethasone was also offered to patients enrolled in the 10 and 20 mg/kg cohorts with less than a partial response to initial therapy with single-agent CP-751,871.ResultsNo CP-751,871-related dose-limiting toxicities were identified. Plasma CP-751,871 concentrations increased with dose and concentration-time profiles were consistent with those of antibodies with target-mediated disposition. Importantly, CP-751,871 administration led to a decrease in granulocyte IGF-IR expression and serum insulinlike growth factor 1 accumulation at high doses, suggesting systemic IGF-IR inhibition. Tumor response was assessed according to the European Group for Blood and Marrow Transplantation criteria. Nine responses were reported in 27 patients treated with CP-751,871 in combination with dexamethasone. Of interest, two of the patients with a partial response were progressing from dexamethasone treatment at study entry.ConclusionThese data indicate that CP-751,871 is well tolerated and may constitute a novel agent in the treatment of multiple myeloma.

Abstract 1633 Background: Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent antitumor antibiotic. CD22 is expressed on the majority of B-cell non-Hodgkin's lymphomas (NHL). This phase 1 study was conducted to identify the maximum tolerated dose (MTD) of INO when given in combination with R-CVP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and vincristine 1.4 mg/m2 all on Day 1 and prednisone 40 mg/m2on Days 1–5) every 21 days, and to obtain preliminary safety and efficacy data for this regimen. Patients and methods: The study enrolled patients with relapsed/refractory CD22+ B-cell NHL. The dose-escalation part (Part 1; previously presented) identified the MTD as INO 0.8 mg/m2 given on Day 2 with R-CVP q3wks [Blood. 2011;118:3715]. Subsequent cohorts included the MTD confirmation cohort (Part 2) and MTD expansion cohort (Part 3), for collection of additional safety and preliminary efficacy data. Untreated patients who were not candidates for anthracyclines were allowed in Part 2 and Part 3 of the study. In Part 2 (n = 10), confirmation of the MTD required a dose-limiting toxicity (DLT) rate of Results: In Parts 2 and 3, a total of 32 patients with follicular lymphoma (FL; n = 15), diffuse large B-cell lymphoma (DLBCL; n = 16), or mantle cell lymphoma (n = 1) were enrolled. CD22 expression was confirmed by immunohistochemistry or flow cytometry prior to enrollment. The median age was 65 years (range, 44–81 years); 34% of patients had 1 prior anti-lymphoma regimen, 34% had 2, 28% had ≥3, and 3% (n = 1) had no previous therapy (median, 2; range, 0–6). The median number of cycles received was 5 (range, 1–6). In Part 2, the MTD was confirmed as standard-dose R-CVP plus INO 0.8 mg/m2, with 2 of 10 patients presenting with a DLT (grade 3 increase in alanine/aspartate aminotransferases [ALT/AST] and grade 4 neutropenia requiring granulocyte-colony stimulating factor). Four patients discontinued due to AEs after 2 cycles (n = 1), 3 cycles (n = 2), and 5 cycles (n = 1), respectively. Across Parts 2 and 3, the most common treatment-related AEs (all grades) were thrombocytopenia (78%), neutropenia (66%), fatigue (53%), constipation (50%), leukopenia (50%), and nausea (41%); the most common grade 3/4 AEs included neutropenia (63%), thrombocytopenia (53%), leukopenia (38%), lymphopenia (31%), increased ALT (9%), increased AST (6%), and febrile neutropenia (6%). There was 1 case of treatment-related fatal pneumonia associated with grade 4 neutropenia. Ten patients discontinued study treatment due to AEs, with thrombocytopenia or delayed recovery from thrombocytopenia being the leading AE causing study drug discontinuation (n = 9 [grade 1/2, n = 6; grade 3/4, n = 3]). The best overall response (ORR; partial + complete response [CR]) from Part 2 and 3 (31 evaluable patients) was 77% (n = 24/31), including 29% (n = 9/31) with CR. Of patients with FL, the ORR was 100% (n = 15/15), including 53% (n = 8/15) with CR. Of patients with DLBCL, the ORR was 60% (n = 9/16), including 7% (n = 1/16) with CR. Conclusions: Results from this phase I study showed that R-CVP in combination with INO 0.8 mg/m2 may have acceptable toxicity and promising activity in patients with relapsed or refractory CD22+ B-cell NHL, based on the response rates in FL and DLBCL. The most common grade 3/4 AEs were hematological toxicities, notably thrombocytopenia and neutropenia. Follow-up for progression-free survival and overall survival is currently ongoing; however, the observed results warrant additional study in both indolent and aggressive B-cell NHL. Disclosures: Ogura: Pfizer Inc: Research Funding. Hatake:Pfizer Inc: Research Funding. Davies:Pfizer Inc: Research Funding. Crump:Pfizer, Celgene, Roche, Millennium, Seattle Genetic: Membership on an entity's Board of Directors or advisory committees. Tobinai:Merck, Zenyaku, Symbio, Biomedics, Pfizer, GSK, Chugai/Roche: Research Funding. Smith:Pfizer Inc: Research Funding. Offner:Pfizer Inc: Research Funding. Wang:Pfizer Inc: Employment, Equity Ownership. Ishibashi:Pfizer Inc: Employment, Equity Ownership. Paccagnella:Pfizer Inc: Employment, Equity Ownership. Vandendries:Pfizer Inc: Employment, Equity Ownership. MacDonald:Roche Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract 3715 Background: Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent antitumor antibiotic. CD22 is expressed on the majority of B-cell non-Hodgkin lymphomas (NHL). Although safety and preliminary efficacy data of INO as monotherapy and in combination with rituximab have previously been reported, there is no report of combination use of INO with chemotherapy. This phase I study evaluated the safety of INO in combination with chemotherapy (R-CVP regimen) in patients with relapsed or refractory CD22+ B-cell NHL. Preliminary efficacy data were also collected. Patients and Methods: Patients with either relapsed or refractory CD22+ B-cell NHL and at least 1 prior treatment regimen, including rituximab and chemotherapy, were enrolled in a phase I dose-finding study (part 1), with a planned expansion cohort (n = 10) to confirm the safety and tolerability of the maximum tolerated dose (MTD; part 2), and a further expansion cohort (n = 20) to estimate antitumor activity (part 3). In the dose-escalation study, INO (0.8 mg/m2) was given on Day 2 with R-CVP (rituximab 375 mg/m2, vincristine 1.4 mg/m2, and escalating doses of cyclophosphamide 375, 550, and 750 mg/m2 all on Day 1; prednisone 40 mg/m2 on Days 1–5) q3wks. After the highest dose of cyclophosphamide was evaluated for safety, INO was escalated to 1.3 mg/m2. Dose reductions and/or dose delays were performed, as needed, based on toxicities. The current analysis presents the completed dose-escalation phase, with preliminary safety and efficacy data. Results: 23 patients with follicular (FL; n = 15), mantle cell (n = 3), diffuse large B-cell (n = 3), or small lymphocytic (n = 1) lymphomas (missing diagnosis, n = 1) have been enrolled so far: 65% of patients were male, and the median age was 62 years (range, 42–74 years). In part 1 of the study, approximately 50% of patients had received 2 or more prior chemotherapy regimens, and all had received prior rituximab. As of the time of this analysis, 11 patients had completed at least 5 treatment cycles (ie, ≥105 days on study drug). No dose-limiting toxicities (DLTs) were reported with INO 0.8 mg/m2 plus R-CVP at the lower doses of cyclophosphamide (375 and 550 mg/m2). At a dose level of INO 0.8 mg/m2 plus full-dose R-CVP (cyclophosphamide 750 mg/m2), 1 out of 6 patients had a DLT of grade 4 neutropenia requiring treatment with granulocyte colony-stimulating factor (G-CSF). At a dose level of INO 1.3 mg/m2 plus R-CVP, 2 out of 3 patients had a total of 3 DLTs (acute hepatitis, thrombocytopenia, and neutropenia requiring G-CSF). Therefore, the MTD was determined to be rituximab 375 mg/m2, vincristine 1.4 mg/m2, and cyclophosphamide 750 mg/m2 all given on Day 1, INO 0.8 mg/m2 given on Day 2, and prednisone 40 mg/m2 given on Days 1 through 5 of each 3-week cycle. Treatment-emergent grade ≥3 adverse events included neutropenia (57%), lymphopenia (52%), leukopenia (35%), thrombocytopenia (30%), increased alanine aminotransferase (9%), increased aspartate aminotransferase (4%), decreased blood sodium (4%), fatigue (4%), febrile neutropenia (4%), hyperbilirubinemia (4%), hypoxia (4%), lethargy (4%), pleural effusion (4%), and pollakiuria (4%). Enrollment is continuing in parts 2 and 3 of the study. Preliminary efficacy data from the escalation portion of the study (n = 15 evaluable patients) is notable for an overall response rate (ORR) of 87% (33% with complete response; 53% with partial response). In patients with FL, the ORR was 100% (45% with complete response). Conclusions: INO 0.8 mg/m2 appears to be tolerable when given in combination with full dose R-CVP chemotherapy. DLTs were hematologic and hepatic, and encouraging signs of antitumor activity have been reported. Disclosures: MacDonald: Roche Canada: Honoraria, Research Funding. Davies:Pfizer Inc: Research Funding. Sangha:Roche: Honoraria; Boehringer Ingelheim: Honoraria. Crump:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche Canada: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria. Thieblemont:Assistance Publique - Hôpitaux de Paris: Employment; Institut National du Cancer - INCa [French National Cancer Institute]: Research Funding. Ishibashi:Pfizer Inc: Employment, Equity Ownership. Hua:Pfizer Inc: Employment, Equity Ownership. Paccagnella:Pfizer Inc: Employment, Equity Ownership, Patents & Royalties. Vandendries:Pfizer Inc: Employment, Equity Ownership. Kobayashi:Ohtsuka Pharmaceutical: Research Funding; Nippon Shiyaku: Honoraria; BMS: Honoraria. Tobinai:Bayer: Research Funding; Celgene: Research Funding; Chugai: Research Funding; Eli Lilly: Research Funding; Genzyme: Research Funding; GSK: Research Funding; Kyowa Hakko Kirin: Research Funding; Janssen: Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Novartis: Research Funding; Pfizer Inc: Research Funding; Symbio: Research Funding; Zenyaku: Research Funding.