Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides or Sezary Syndrome: Final Results Show Significant Clinical Activity and Suggest Correlation with CD30 Expression

Background: Brentuximab vedotin (BV) is an anti-CD30 chimeric antibody conjugated by a protease-cleavable linker to the microtubule-disrupting agent, MMAE. While CD30 expression of malignant cells in HL and ALCL is uniform, in mycosis fungoides/Sezary syndrome (MF/SS), the CD30 expression is more variable. We reported previously (ASH 2012) that BV has clinical activity in MF/SS across all CD30 expression levels. In this final report, we update the clinical data and present new biomarker and correlative tissue analyses. Methods: Patients (pts) with MF/SS stages IB-IV, ECOG 0-2, with at least 1 prior systemic therapy were enrolled in this investigator-initiated, phase II, single-arm study. CD30 expression levels in the skin (% of total mononuclear cell infiltrate) were evaluated by routine immunohistochemistry (IHC) using the BerH2 antibody. At least 2 skin biopsies were obtained per pt and the max CD30 level was used for CD30 designation. All pts (CD30, 0-100%) were treated with up to 8 cycles of BV (1.8 mg/kg) administered every 3 weeks; optional extension of up to 8 additional cycles was allowed in responders with ongoing clinical improvement. Primary endpoint was overall response rate (ORR) by consensus global response criteria. CD30 expression and clinical response data were confirmed by independent review. Tumor microenvironment was assessed utilizing IHC for CD8, CD20, CD163, FoxP3, and PD-1. Multispectral image analysis was utilized to evaluate CD30 antigen co-expression. Results: 32 pts were enrolled and all received at least one dose of BV (Table); all included in safety data, 2 excluded in efficacy analyses (no response assessment). Median age was 62 (20-87). 28/32 (88%) had advanced disease, majority with adverse prognostic features (90% large cell transformation or folliculotropism). ORR was 70% (21/30) with responses in all clinical stages. Median best mSWAT reduction (response measure in the skin) was 73% (range, 100% to -54%) with 1 CR, 7 near CR in skin (>90% reduction) (Fig 1). Median time to response was 6.6 weeks (range 3.0-27.0). Kaplan-Meyer estimate shows 79% of responses ongoing and 54% progression-free at 12 months. Related AEs observed were mostly grade 1-2 and limited to AEs previously reported with BV. By IHC, median max CD30 expression level of all pts was 13% (range 0-100%; 6 had <5%), where the median was higher in responders (CR/PR), 15%, vs. non-responders (SD/PD), 3.0%, p=0.037 (Fig 1). The correlation with CD30 level was greatest in IIB/skin tumor subset (p=0.0072). Those with CD30 level <5% had a lower likelihood of clinical response (17% vs 83%; p=0.0046). Multispectral image analysis demonstrated quantifiable CD30 staining in 19/20 (95%) samples that were interpreted as negligible CD30 by routine IHC. Of other tissue biomarkers evaluated, CD163+ cells (macrophages) were most abundant with a median of 40% (range 5-80%) of total infiltrate. To distinguish expression of CD30 by neoplastic CD4+ vs. tumor-infiltrating cells, double staining for CD30 and CD8 or CD163 was assessed. We observed significant co-expression of CD30 by CD163+ macrophages (median 9.7% of total cells assessed, range 1.0-40.9%) or CD8+ cytotoxic T cells (median 1.7%, range 0.2-14.8%) (Fig 2). Those with lower CD163 relative to CD30 stain (CD163/CD30 ratio) by routine IHC were associated with clinical response (p=0.033). This may simply reflect the influence of CD30 level; however, in light of the co-localization data, it might also suggest that infiltrating macrophages that co-express CD30 may play a role as a microenvironment factor in clinical response to BV. Conclusions: Our final analysis confirms significant clinical activity of BV in MF/SS with expected AE profile. Although clinical response was observed at all levels of CD30 expression, the likelihood of response was lower in those with negligible or very low (<5%) level. We utilized multispectral imaging to enhance detection of CD30 and also show co-expression of CD30 by tumor-infiltrating cells. These findings suggest that further studies of biomarkers are warranted and may help optimize management strategies with BV. Table Characteristic All Pts n=32 Evaluable n=30 ORR n (%) n (%) CR PR SD PD Clinical Stage All pts IB IIB IV/SS 32 (100) 4 (13) 18 (56) 10 (31) 1 0 0 1 20 3 14 3 4 1 2 1 5 0 2 3 21/30 (70) 3/4 (75) 14/18 (78) 4/8 (50) Transformed or folliculotropic MF 29 (91) 1 19 3 5 20/28 (71) # prior systemic tx <3 >=3 15 (47) 17(53) 0 1 8 12 2 2 4 1 8/14 (57) 13/16 (81) Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Kim: Actelion: Consultancy; Celgene: Advisory, Advisory Other; Eisai: Research Funding, SAC/Advisory, SAC/Advisory Other; Galderma: Advisory, Advisory Other; Millennium/Takeda: Research Funding, SAC/Advisory Other; Kyowa-Hakko-Kirin: Research Funding, SAC/Advisory Other; Oncosec: Advisory Other; Seattle Genetics: Advisory, Advisory Other, Research Funding; SHAPE: Consultancy, Research Funding. Off Label Use: Treatment of cutaneous T-cell lymphoma, also recently added to NCCN NHL practice guidelines in CTCL. Wood:Millennium: IDMC Other. Advani:Seattle Genetics: Research Funding. Horwitz:Millennium: Consultancy, Research Funding; Infinity: Research Funding; Kiowa-Kirin: Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Research Funding; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding.

A phase I study of cediranib (NSC #732208) in combination with cisplatin and pemetrexed in chemonaive patients with malignant pleural mesothelioma (SWOG S0905).

7527 Background: The VEGF/VEGFR and PDGF/PDGFR pathways are potential therapeutic targets in mesothelioma. Cediranib, a VEGFR/PDGFR inhibitor, showed anti-tumor activity in a salvage monotherapy study S0509. Methods: S0905 combined cediranib (2 dose cohorts 30 mg and 20 mg daily) with cisplatin and pemetrexed for 6 cycles followed by maintenance cediranib in unresectable chemo-naïve MPM patients. Results: A total of 20 patients (7 to cohort 1 - 30 mg, 13 to cohort 2 - 20 mg) were enrolled. In first cohort, 2 patients reported grade 3 DLTs of diarrhea and fatigue. Cohort 2 DLTs included 2 patients with grade 3 hyponatremia/dehydration and mucositis. For all cycles, 12 patients reported Grade 3 AEs, the most common being diarrhea (4), dehydration (3), fatigue (3) and neutropenia (3). Two grade 4 thrombocytopenia were reported with 1 treatment-related death (cohort 2) due to pneumonia/sepsis. Based on the toxicity profile, a decision was made to proceed with cediranib 20 mg daily for the remaining phase I/II trial. Two radiographic response measurements were utilized (RECIST 1.1, modified RECIST). 18/20 patients were evaluable for response by RECIST 1.1 (7 - 30 mg cohort, 11 - 20 mg cohort). The RECIST 1.1 RR was 22% (95% CI: 6% - 48%) and median PFS was 14 months (95% CI: 8 – 17). Two patients had inadequate assessments and are classified as non-responders. There were 19 patients measurable by modified RECIST with RR 53% (95% CI: 29%-76%) and median PFS 10 months (7-13). For all patients, the median OS was 16 months (95% CI: 11-19). One patient in the 30 mg cohort remains on trial after 25 cycles of therapy; 2 patients at the 20 mg cohort remain on trial on cycles 19 and 15 of therapy. Conclusions: Cisplatin-pemetrexed-cediranib shows significant clinical activity and acceptable toxicity with cediranib 20 mg/day. The randomized phase II portion of the trial is ongoing. Clinical trial information: NCT01064648. [Table: see text]

Brentuximab Vedotin Demonstrates Significant Clinical Activity in Relapsed or Refractory Mycosis Fungoides with Variable CD30 Expression

Abstract 797 Background: Brentuximab vedotin (BV) is an anti-CD30 chimeric antibody conjugated by a protease-cleavable linker to the microtubule-disrupting agent monomethyl auristatin E. BV received accelerated FDA approval in 2011 for relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL). While CD30 expression of malignant cells in HL and ALCL is uniform, in mycosis fungoides/Sezary syndrome (MF/SS), the CD30 expression is more variable. Given the tumor selectivity and possible bystander effects, we explored the clinical activity of BV in this group of patients with variable CD30 expression and assessed for correlation of CD30 expression and response. Methods: Patients with age 18 or older, MF/SS stages IB-IV, ECOG performance status 2 or lower, and with at least 1 prior systemic therapy were enrolled in this investigator-initiated, phase II, single-arm exploratory study. CD30 expression levels in the skin (proportion of total lymphoid infiltrate) were evaluated by routine immunohistochemistry (IHC) using the BerH2 antibody. Subjects, irrespective of pre-treatment CD30 staining, were treated with up to 8 cycles of brentuximab vedotin (1.8 mg/kg) administered every 3 weeks; optional extension of up to an additional 8 cycles was allowed in responders with ongoing clinical improvement. Global response was determined according to consensus response criteria in MF/SS. CD30 expression and clinical response data were confirmed by independent review. Results: 19 subjects were consented and all received at least one dose of BV; median age was 59 (range 20–88) with a median of 4 prior systemic therapies (range: 1–13), with the majority having advanced disease and/or adverse prognostic risk factors (17/19 Stage IIB or greater, 13/19 large cell transformation (LCT), 8/19 folliculotropic MF (FMF), and 3/19 both LCT and FMF). Pre-treatment IHC CD30 expression (% positive of total lymphoid infiltrate) in skin biopsies was used to define three subject groups: < 10% (n=7); 10–50% (n=10); >50% (n=2). The overall response rate was 68% (13/19). Median best mSWAT reduction (response measure in the skin) was 65%. Responses were observed in all clinical stages: Stage IB (2/2 PR), Stage IIB (10/11 PR, 1/11 SD), Stage IVA/B (1/6 PR, 1/6 SD, 4/6 PD). Median time to response was 6 weeks (range 3–18). At 25 weeks, Kaplan-Meyer estimate shows 74% of responses are continuing and 73% are progression-free at time of analysis with median study follow-up time of 36 weeks (range 6–55). The median event free survival, with event defined by progressive disease, early study termination, or initiating another significant treatment was 27 weeks (range 5–47+). Related grade 1 or 2 adverse events (AEs) occurring in >20% were peripheral neuropathy (78%), fatigue (61%), decreased appetite (28%), and nausea (22%). Grade 3–4 related AEs included rash (n=3), neutropenia (n=2), and single reports of lymphocytosis, peripheral neuropathy, pruritus, pneumonia, hyperglycemia, sepsis, acute renal failure, leukopenia, and thrombocytopenia. One death was reported due to respiratory failure in the patient with pneumonia. Time to development of neuropathy was median 14 weeks (range: 6–39) and the median time to resolution or improvement in neuropathy (from onset of neuropathy) was 24 weeks (range 6–46+). Pre-treatment CD30 quantitative image analysis (Nuance imaging system, CRi, Woburn, MA) staining data were available for 31 biopsy samples from 16 of 19 subjects. Evaluation by quantitative image analysis detected CD30 staining of lymphoid cells in all samples including 12 interpreted as negative by routine IHC, as well as 3 from tumors that developed while on BV. CD30 expression levels did not correlate with clinical response as assessed by routine IHC (p=0.17) or image analysis (p=0.74). Conclusions: Our exploratory study demonstrates significant clinical activity of brentuximab vedotin in heavily pre-treated MF with mostly grade 1/2 related AEs. Clinical responses were observed in those with all levels of CD30 expression. Responses in subjects with zero to low CD30 expression by routine IHC may be in part due to low sensitivity of standard IHC detection of drug target. This study reports the successful utility of multispectral image analysis to demonstrate low levels of target expression. Disclosures: Off Label Use: Brentuximab vedotin is not approved for use in mycosis fungoides / Sezary syndrome. BV is an anti-CD30 antibody conjugated to the anti-tubulin inhibitor MMAE. It is approved for use in relapsed Hodgkin Lymphoma and systemic anaplastic large cell lymphoma. Advani:Seattle Genetics: Research Funding. Nagpal:Seattle Genetics: Consultancy. Horwitz:Seattle Genetics: Consultancy, Research Funding. Kim:Seattle Genetics: Consultancy, Honoraria; Millenium Pharmaceuticals: Consultancy, Honoraria.

Phase I Study of Clofarabine with Standard-Dose Infusional Cytarabine (Ara-C) as Intensive Induction Therapy for Newly-Diagnosed De Novo Acute Myeloid Leukemia in Older Adults Age ≥60 Years.

Background The median age of AML is approximately 70 years, and the survival of older adults age ≥60 years remains poor with standard therapy. Clofarabine (CLO) has significant single agent activity in AML, and in vitro studies demonstrate synergy with Ara-C. We therefore performed a phase I study to determine the maximum tolerated dose (MTD) of CLO with standard dose Ara-C (100mg/m2/day D1-7 by 24hr continuous infusion) as AML induction therapy. CLO was administered daily × 5 days beginning D2 to allow for pharmacokinetic (PK) & pharmacodynamic (PD) studies. Methods Enrollment was restricted to newly-diagnosed de novo AML patients age ≥60 years considered candidates for intensive therapy; those with prior MDS or hypoplastic AML (&lt;20% bone marrow cellularity) were excluded. Pts were treated in cohorts of 3–6 to determine MTD of CLO with standard dose infusional Ara-C (100mg/m2 × 7). DLT was defined as grade III/IV non-hematologic toxicity occurring in &gt;1 pt per cohort. The CLO starting dose was 30mg/m2/day ×5 (dose level 1), with the intention to increase to CLO 40mg/m2 if tolerated. However, CLO dose reductions of 25% (CLO 22.5 mg/m2/day × 5, dose level -1) & 50% (CLO 15mg/m2/day ×5, dose level -2) were allowed in the event of dose-limiting toxicity (DLT). Pts achieving complete remission (CR) received 2 cycles consolidation with CLO ×5 & Ara-C 100mg/m2 × 5. Results A total of 13 pts (median age 69 yrs, range 61–77; 10 male) have been treated. DLT was observed at dose level 1 (Table 1), and the protocol was amended to mandate additional hydration with CLO, and antibiotic/antifungal prophylaxis. At dose level -1, 1 pt died from PE on D27 after hematologic recovery, considered treatment-related per protocol, mandating dose de-escalation to dose level -2. Pt 13 is in active induction therapy, and not yet evaluable for response, although DLT has not been encountered. Febrile neutropenia occurred in 11/13 pts. The MTD in this study is CLO 15mg/m2/day × 5 with standard infusional Ara-C (dose level -2). Significant clinical activity was observed, particularly at higher CLO doses, including CR in 2 pts with complex karyotype. In contrast, only 1/5 evaluable pts at dose level-2 achieved CR. PK & PD studies are in progress. Conclusions In contrast to prior reports using intermediate dose bolus Ara-C (1g/m2), the MTD of CLO combined with standard dose infusional Ara-C in older adults with AML is lower, and the toxicity profile appears different. Significant clinical activity was noted at higher CLO dose levels & with complex karyotype. Based on this observation an escalation to CLO 20mg/m2 is now planned. CLO & Standard Dose Infusional Ara-C: Toxicity & Efficacy Patient CLO Dose Level Age Cytogenetics Response (CR Duration) DLT Fail - failure to achieve CR 1 1 (30mg) 66 −7 Death Infection/Renal 2 1 61 −7, complex CR (15 mths) none 3 1 69 intermediate CR (2 mths) none 4 1 77 5q-, complex Death Infection/Renal/Vasc Leak 5 −1 (22.5mg) 75 +8 Death Pneumonia 6 −1 67 diploid CR (5 mths) none 7 −1 71 9q- Death Pulm Embolism Day 27 8 −2 (15mg) 74 5q-, complex Fail none 9 −2 64 diploid Fail none 10 −2 63 diploid Fail none 11 −2 73 complex CR (5 mths) none 12 −2 72 diploid Fail none 13 −2 63 diploid - -

The Combination of Velcade, Idarubicin and Melphalan (VIM) Demonstrates Significant Clinical Activity in Relapsed/Refractory Myeloma Patients.

Dexamethasone is an important drug in the treatment of myeloma and is widely used in novel combinations, however, resistance can develop and clinical intolerance is frequent. Novel regimens that are effective and dexamethasone sparing are therefore required. Bortezomib (Velcade), the first-in-class proteasome inhibitor, has shown to be effective for the treatment of relapsed refractory myeloma, and has been shown to enhance the antitumor efficacy of both Melphalan and Anthracyclines. Early clinical results have demonstrated the efficacy and tolerability of combinations of Velcade with either of these agents. We have carried out a dose-escalating phase 1 study is to assess the safety, tolerability and response rate of the Velcade/Idarubicin/Melphalan (VIM) combination. Patients with relapsed/refractory myeloma who were either resistant or intolerant to dexamethasone were recruited. The study aimed to recruit 6 cohorts of 3 patients with standard dose Velcade and increasing doses of Melphalan and Idarubicin. Velcade (1.3 mg/m2) was administered on days 1, 4, 8 and 11 on a 28-day cycle with total number of 3 cycles, with the single dose of Melphalan (10, 15 or 20 mg/m2, i.v.) on day 4 and Idarubicin (5 or 10mg/m2) on days 4,5,(6 and 7). NCI CTCAE v3.0 was used for toxicity assessment; DLT was defined as any grade 3 or 4 non-haem toxicity (excluding neuropathy) or any grade 4 haem toxicity (excluding neutropenia) which does not resolve to a grade 2 within 2 weeks of completing a course. As of July 2007, 14 patients were enrolled in cohorts 1–3 with a median age of 59 (range 36–68). The median number of prior therapies was 2.5 (range 1–5), including 10 pts with prior high dose therapy, 11 with Anthracyclines, and 13 with Thalidomide. In patients assessable for response 9/13 achieved a response with 2 CR, 5 PR and 2 MR according to EBMT criteria. The side effect profile was manageable and no unexpected toxicities were seen. Grade 3 toxicities were mostly related to myelosuppression with 79% thrombocytopenia and 71% neutropenia. 12 patients received GCSF to maintain their neutrophil count and 10 pts received platelet transfusions. Despite the myelosuppression no increase in infections or serious bleeding was observed. 5 patients required a dose reduction of Velcade and/or course delay due to low counts and 1 patient also required Melphalan dose reduction. Other side effects included upper respiratory tract infection (36%), peripheral neuropathy (29%) and shingles (14%), resulting in a recommendation of aciclovir prophylaxis for all patients. New/worsening neuropathy led to dose reduction of Velcade in 2 patients and discontinuation of treatment in 1 patient. One DLT of G3 respiratory tract infection was observed in cohort 3 (Mel 15 mg/m2, Idarubicin 5 mg/m2 on day 4–7), therefore another 3 patients will be enrolled to this cohort. The study indicates that VIM had a manageable toxicity profile with significant clinical activity in this dexamethasone refractory group of patients.