Refractory CD30-positive Lymphoma Research Articles

A multi-center and non-interventional registry of brentuximab vedotin in patients with relapsed or refractory CD30-positive lymphoma: the CISL1803/BRAVO study.

Brentuximab vedotin (BV), a potent antibody-drug conjugate, targets the CD30 antigen. In Korea, BV has been approved for the treatment of relapsed or refractory Hodgkin lymphoma (HL), anaplastic large-cell lymphoma (ALCL), and cutaneous T-cell lymphomas, including mycosis fungoides (MF). However, there are limited data reflecting real-world experiences with BV treatment for HL, ALCL, and MF. This was a multicenter, non-interventional registry study of the efficacy and safety of BV in patients with relapsed or refractory CD30-positive lymphoma (CISL1803/BRAVO). Outcomes were determined based on the occurrence of relapse or progression and overall survival after BV treatment. A total of 85 patients were enrolled in this study. The median number of BV cycles was 10 (range, 2‒16) in the patients with HL. The objective response rate (ORR) of patients with HL to BV was 85.4% (41/48), comprising 27 complete responses (CRs) and 14 partial responses (PRs). The ORR of ALCL was 88% (22/25), consisting of 17 CRs and five PRs, whereas the ORR of MF was 92% (11/12). At the median follow-up of 44.6 months after BV treatment, the median post-BV progression-free survival of HL, ALCL, and MF patients was 23.6 months, 29.0 months, and 16.7 months, respectively (P=0.641). The most common side effect of BV was peripheral neuropathy; 22 patients (25.9%, 22/85) experienced peripheral neuropathy (all grades). The treatment outcomes of patients with relapsed or refractory CD30-positive lymphoma improved with BV treatment, and the safety profile was manageable.

Innate Cell Engager (ICE®) AFM13 Combined with Preactivated and Expanded (P+E) Cord Blood (CB)-Derived Natural Killer (NK) Cells for Patients with Refractory CD30-Positive Lymphomas: Final Results

CONCLUSIONS Pts with refractory Hodgkin (HL) and other CD30+ lymphomas have few effective therapies available and targeted NK cell immunotherapy is an active area of research. Transfer of non-targeted NK cells has shown limited clinical benefit as target recognition of cancer cells by NK cells constitutes a barrier. The innate cell engager AFM13 is a first-in-class CD30/CD16A bispecific antibody construct that induces selective killing of CD30+ tumor cells by engaging and activating NK cells. As a single agent, AFM13 has limited clinical activity against HL, likely due to the reduced effector function of autologous NK cells in these pts, which provides the rationale for combining AFM13 with allogeneic NK cells. Our prior preclinical work identified a promising combination of CB-derived NK cells that were first IL-12/IL-15/IL-18-preactivated followed by ex vivo expansion (P+E) with engineered K562 feeder cells expressing membrane-bound IL-21, 4-1BBL and CD48 and exogenous IL-2, and subsequently complexed with AFM13 just before infusion; these cytokine-induced memory-like NK cells presented chimeric antigen receptor (CAR)-NK-like features and increased in vitro and in vivo antitumor activity compared to either non-AFM13-precomplexed P+E NK cells or to AFM13 alone (Kerbauy et al, Clin Cancer Res 2021). Building on this work we wished to study this CB NK-cell therapy in pts with refractory CD30+ lymphomas. This investigator-initiated single-center phase I-II trial (NCT04074746) evaluated the safety and activity of P+E AFM13-precomplexed CB NK cells followed by systemic AFM13. Pts ages 15-75 with CD30+ lymphomas refractory to brentuximab vedotin were enrolled. The goals were to identify the recommended phase 2 dose (RP2D) of NK cells, estimate the overall (ORR) and complete response (CR), event-free (EFS) and overall survival (OS) rates, and study NK cell activation and persistence. Each treatment cycle consisted of fludarabine/cyclophosphamide (days −5 to −3) followed by infusion (day 0) of the AFM13-precomplexed CB NK cells, cultured for 14 days as described above, and three weekly IV infusions of AFM13 (200 mg, days 7, 14 and 21). Two cycles were planned for pts 1-19 and up to 4 cycles from patient 20 on. Response was evaluated on day 28 of each cycle. Enrollment proceeded at 3 dose levels (DL) of 10 6, 10 7 and 10 8 NK/Kg, respectively. Each patient received the same NK dose in all cycles. Between 09/20-12/22 we enrolled 42 pts (37 HL, 5 NHL), pretreated with a median 7 lines, at DL1 (N=3), DL2 (N=3) and DL3 (N=36), with 1 (N=2), 2 (N=21), 3 (N=3) or 4 cycles (N=16). All had active progressive disease at enrollment and no bridging therapy was given. The cords used for each of the 117 cycles were selected without consideration for HLA match, which was 0/6 (N=53), 1/6 (N=46), 2/6 (N=14), 3/6 (N=3) and 4/6 (N=1). The product infused consisted of >94% NK cells (expanded >2,700 fold), with only 0.02% T cells. The NK cells were 96% viable, 91% bound to AFM13, and 97.6% CD16+. The products were infused fresh. There was 1 grade 2 infusion-related reaction (IRR) in 115 infusions of AFM13-NK (0.8%) and 27 IRR infusion related reactions in 350 infusions of AFM13 (7.7%) (1 G3, 26 G2). We saw no cases of CRS, ICANS or GVHD of any grade. DL3 (10 8 NK/Kg) was established as the RP2D. The ORR and CR were 92.8% and 66.7%, respectively (94.4% and 72.2%, respectively, in 36 pts treated at the RP2D). Nine pts had a response consolidated with SCT (5 allo, 4 auto). At median follow-up of 14 (6-34) months, the EFS/OS rates are 31%/76%; median EFS/OS are 8 months/not reached. No relapses were associated with antigen loss. In the subset of pts planned for 4 cycles at RP2D, 15 of 23 pts remained event free at 6 mo (4 pts with and 11 without SCT consolidation), for 6-month EFS/OS rates of 65%/83%. Overall, 8 of the 9 pts (89%) receiving a consolidation SCT are event free at 10 to 34 months. AFM-bound CB NK cells were detected in blood from day 1 post infusion for up to 3 weeks. Donor NK levels followed similar patterns after each cycle, which argues against a sensitization after the first NK infusion. CyTOF studies showed increased expression of AFM13 and activation markers in donor NK cells. We confirmed trafficking of AFM13-bound donor NK cells to tumor sites shortly after infusion. CB-derived cytokine-induced memory-like NK cells precomplexed with AFM13 have excellent tolerability and activity for pts with heavily pretreated and refractory CD30+ lymphoma.

Safety and Efficacy of Off-the-Shelf CD30.CAR-Modified Epstein-Barr Virus-Specific T Cells in Patients with CD30-Positive Lymphoma

Safety and Efficacy of Off-the-Shelf CD30.CAR-Modified Epstein-Barr Virus-Specific T Cells in Patients with CD30-Positive Lymphoma

A Pilot Study of Weekly Brentuximab Vedotin in Patients with CD30+ Malignancies Resistant to Every 3 Week Brentuximab Vedotin

Background:Brentuximab vedotin (BV) is effective in treating of relapsed/refractory CD30 positive malignancies, such as classical Hodgkin lymphoma (CHL) and systemic anaplastic large cell lymphoma (ALCL). BV combines an anti-CD30 monoclonal antibody with a potent anti-microtubule agent, Monomethyl auristatin E (MMAE), disrupting the cell cycle of CD30 positive cells. Patients (pts) with relapsed/refractory CHL and systemic ALCL have shown promising overall response rates (ORR) with BV, but most patients will eventually suffer progressive disease (PD). The mechanism of resistance to BV remains unclear, however, most lymphomas with PD following BV still demonstrate CD30 expression suggesting that it may remain a viable target. Prior clinical data indicate that weekly BV dosing given on Days 1, 8 and 15 of a 28 day cycle was tolerable, had an ORR of 59% and a higher complete remission rate than was seen in a similar phase I trial of 21-day dosing of BV. We, thus, hypothesized that patients with CD30-positive lymphomas who progressed on standard BV dosing may still respond to weekly BV dosing and tested this in a prospective phase II trial. We also quantified CD30 expression to evaluate the impact of BV on CD30 expression and the impact of CD30 on response to BV, and assessed T and NK cell infiltrates for correlation with response.Methods:Eligible pts were age >18 or older with relapsed or refractory CD30 positive lymphoma who had progressed during or achieved less than a partial response following a minimum of 2 cycles of BV. Key inclusion criteria included documented expression of CD30 on tumor cells following the last dose of prior BV, as well as adequate marrow, hepatic and renal function and no major infections. Key exclusion criteria were ECOG > 2, prior transplant within 100 days, radioimmunotherapy within 12 weeks, active CNS involvement, and pre-existing neuropathy > NCI-CTCAE Grade 2 (or > Grade 1 if secondary to prior BV). Each cycle consisted of BV at 1.2 mg/kg (capped at 120mg) given over 30 minutes on Days 1, 8 and 15 every 28 days. Patients with stable disease or better could remain on therapy for up to 4 cycles. CD30 expression was quantified using multiparameter flow cytometry to identify the Hodgkin-Reed-Sternberg (HRS) cells.Results:Eight (8) pts enrolled in the study. The median age was 42 (27-68). The pts were heavily pretreated (median 6 prior lines of treatment) and 63% had undergone autologous transplant (Table 1). Histologies included CHL (7) and ALK-negative systemic ALCL (1). Pts received between 2 to 16 (median 5) prior cycles of Q3 week BV prior to enrolling in the study. All patients suffered eventual progressive disease (PD) on Q3 week BV, though 3 had a transient prior partial response (PR). Weekly BV was well tolerated with only one grade 3 event (hypokalemia). Neuropathy was seen in 5 (63%) pts: 3 Grade 1, 2 Grade 2 resulting in one treatment discontinuation. Two pts completed all 4 BV cycles on study; both had progressive disease after the 4th cycle. Of the 6 pts who terminated the study early, the majority (67%) did so due to progressive disease. One pt had a partial response to BV after 3 cycles (with a 50% decrease in size of target nodes compared to baseline). Reduction in target lesions were seen in 5/7 (71%) response-evaluable patients (Figure 1). The overall response rate (ORR) of 13% triggered the protocol-defined early stopping rule. None of the screened patients were found to have lost CD30 expression following prior BV, however expression only ranged from dim to intermediate by IHC. CD30 surface density was quantified in paired pre and post BV samples from 3 patients and did not show a significant change or correlation with response. NK and T cell infiltrates were not correlated with response.Conclusions:Pts with BV-refractory CD30 positive malignancies can safely receive weekly BV at 1.2 mg/kg dosing given on Days 1, 8 and 15 of a 28-day cycle. Even though a majority demonstrated reduction in target lesions, the response rate was low. Alterations in CD30 density on HRS cells was not observed following BV when quantified by flow cytometry. Elucidation of tumor- and immune-related mechanisms of BV resistance is needed, as BV is poised for increased use earlier in the course of therapy for HL and ALCL. [Display omitted] DisclosuresSmith:Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Sharp: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Dohme Corp: Research Funding; Merck: Research Funding. Gopal:Seattle Genetics: Consultancy, Research Funding.

Title: Clinical and Biological Evaluation of the Novel CD30/CD16A Tetravalent Bispecific Antibody (AFM13) in Relapsed or Refractory CD30-Positive Lymphoma with Cutaneous Presentation: A Biomarker Phase Ib/IIa Study (NCT03192202)

Introduction: Natural Killer cells (NK) play an important role in tumor immune-surveillance. The innate cell engager AFM13 is a CD30/CD16A targeting high affinity bispecific tetravalent antibody that engages and activates NK. This study evaluates AFM13's clinical and immunological activity. It examines the immunologic changes in the tumor and in peripheral blood (PB) as a function of the dose and method of administration of AFM13. Methods: Subjects with relapsed or refractory CD30 expressing lymphoma with cutaneous involvement were recruited into 4 cohorts: 1.5 mg/kg IV weekly, 7 mg/kg IV weekly, 7 mg/kg continuous intravenous infusion (CIVI) over 5 days weekly and 200mg IV weekly. Each cohort consisted of 3 subjects with 3 additional subjects in cohort 4. Subjects received 8 weeks of therapy for up to 2 cycles. Response assessment was performed on week 11 of each cycle by mSWAT, photography, PET imaging and PB flow cytometry. A second cycle was administered if there was no progression. Subjects underwent skin biopsies and PB immunologic studies as follows: pretreatment, day 5, week 4 and week 8 of therapy. Biopsies were analyzed and evaluated by a pathologist and IHC image analyzer. PB samples were analyzed by flow cytometry. Results: Fourteen subjects were accrued. The median number of prior therapies was 4 (1-11) and 4 subjects had progressed on brentuximab vedotin. The disease etiologies, treatment emergent toxicities and response by cohort are presented in Table 1. An objective response rate of 40% was observed in the study. In the PB, flow cytometry revealed a decrease in circulating NK (CD16/56+ CD3- CD19- lymphocytes) during therapy with post therapy recovery. The activation marker CD69 on NK increased in responders (R) compared to non-responders (NR). Similarly, tumor biopsies in R showed increased infiltration and activation of CD56+ NK as opposed to NR (Figure 1). NK cytotoxicity through the expression of Granzyme B was seen in R vs. NR. Flow quantitation of circulating CD4+ CD25+ T cells (Tregs) showed a decrease in R vs. NR. Conclusions: AFM13 demonstrated a high ORR of 40% among a population of heavily pretreated subjects with CD30 positive lymphoproliferative T-cell malignancies. AFM13 exhibited activity post brentuximab vedotin failure. In addition, biological changes in NK infiltration and activation in the PB and tissue biopsy correlated with response. These data are the first to demonstrate that innate cell engagers modulate NK and T cell populations in the peripheral blood and tumor from patients and to determine that such changes are associated with patient benefit. Disclosures Sawas: Roche: Current equity holder in publicly-traded company; Affimed: Research Funding; Daiichi Sankyo: Speakers Bureau; Seattle Genetics: Speakers Bureau; Gilead: Speakers Bureau; Flatiron Health: Current Employment. Chen:Affimed: Research Funding. Lipschitz:Affimed: Research Funding. Rodig:Bristol Myers Squibb: Research Funding; Merck: Research Funding; Affimed: Research Funding; KITE/Gilead: Research Funding; Immunitas: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees.

Clinical and Biological Evaluation of the Novel CD30/CD16A Tetravalent Bispecific Antibody (AFM13) in Relapsed or Refractory CD30-Positive Lymphoma with Cutaneous Presentation: A Biomarker Phase Ib/IIa Study (NCT03192202)

Introduction: Natural Killer cells (NK cells) play an important role in tumor immune-surveillance. NK-mediated cell killing can occur through distinct mechanisms: (1) by activating the receptor NKG2D and natural cytotoxicity receptors (NCR), and (2) through the potent activating receptor CD16 (FcγRIII) which mediates antibody-dependent cell-mediated cytotoxicity (ADCC). Therapeutic strategies to harness the ability of NK cells to induce an ADCC response are emerging. AFM13 is a CD30/CD16A targeting high affinity bispecific tetravalent antibody that engages and activates NK cells. This study evaluates the ability of AFM13 to engage innate immunity through specific activation and recruitment of NK cells to tumors expressing CD30 and the impact of these effects on clinical outcome. In addition, it examines the immunologic changes in the tumor and peripheral blood as a function of the dose and method of administration of AFM13 over time.Methods: Subjects with relapsed or refractory CD30 expressing lymphoma with cutaneous involvement were recruited into 3 treatment cohorts: (1) 1.5 mg/kg IV weekly, (2) 7 mg/kg IV weekly and (3) 7 mg/kg continuous intravenous infusion (CIVI) over 5 days weekly. Each cohort consisted of 3 patients. Subjects received 8 weeks of therapy each cycle. Response assessment was performed on week 11 of each cycle by mSWAT, photography, PET imaging and peripheral blood flowcytometry. A second cycle was administered if there was no progression of disease. Subjects underwent mandatory tumor biopsies and peripheral blood immunologic studies during the first cycle of therapy as follows: pretreatment, day 5 post first dose, week 4 and week 8 of therapy. An optional biopsy was also collected at end of study. Tumor biopsies were analyzed and evaluated by a pathologist and IHC image analyzer to characterize immune cell subpopulations. Peripheral blood samples were analyzed by flowcytometry.Results: Nine subjects were accrued. Their age ranged from 37-79 years, 3 of 9 where white and 6 of 9 were men. The median number of prior therapies was 4 (1-11), 2 patients had progressed on Brentuximab vedotin, and 5 patients received total skin electron beam radiotherapy. The disease etiologies were as follows: 4 patients with transformed mycosis fungoides, 2 patients with systemic anaplastic large cell lymphoma-ALK negative, 2 patients with non- transformed mycosis fungoides and 1 patient with cutaneous anaplastic large cell lymphoma.Among the 8 subjects who were evaluable for response 4 of 8 (50%) achieved an objective response rate (ORR). In cohort 1 we observed 1 complete response (CR), 1 partial response (PR) and 1 stable disease (SD). In cohort 2, we observed 3 SD. In cohort 3, we observed 2 PRs and one subject awaiting disease assessment. Infusion related reaction (IRR) were observed in 4 of 9 subjects and managed conservatively. Cellulitis was noted in 3 subjects of which 2 developed bacteremia requiring intravenous antibiotics, and was not considered related to AFM13 treatment. There were no other treatment-emergent adverse events.In the peripheral blood, we observed a decrease in circulating NK cells during therapy (Weeks 1- 8) with post therapy recovery (by week 11) by following cells that were CD56+ CD3- , CD56+ CD16+ and NKp46+ by Flow Cytometry. We observed an increase over time in the expression of the activation marker CD69 on NK cells from responders compared to non-responders. Similarly, tumor biopsies in responders showed increased infiltration of CD56+ NK cells as opposed to non-responders. Flow quantitation of circulating CD4+ CD25+ T cells (Tregs) shows a decrease in responders vs. non-responders.Conclusions: AFM13 demonstrated a high ORR of 50 % among a population of heavily pretreated patients with a CD30 positive lymphoproliferative T-cell malignancy. AFM 13 exhibited activity post Brentuximab vedotin failure. In addition, biological changes in NK cells may predict response. This data are the first to demonstrate the therapeutic advantages of this bispecific, and the first to correlate changes in NK cells as a function of dose and schedule. AFM13 is able to engage the innate immune system through a specific activation and recruitment of circulating NK cells to tumors expressing CD30. This immunological tumor response may correlate with clinical response. We have begun to expand the patient cohorts, and pursue additional comprehensive correlative studies in this population. DisclosuresRodig:KITE: Research Funding; Bristol Myers Squibb: Research Funding; Affimed: Research Funding; Merck: Research Funding. O'Connor:Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding; Celgene: Research Funding.

415. First-In-Patient Proof of Safety and Efficacy of a 4th Generation Chimeric Antigen Receptor-Modified T Cells for the Treatment of Relapsed or Refractory CD30 Positive Lymphomas

415. First-In-Patient Proof of Safety and Efficacy of a 4th Generation Chimeric Antigen Receptor-Modified T Cells for the Treatment of Relapsed or Refractory CD30 Positive Lymphomas

Complete remission in CD30-positive refractory extranodal NK/T-cell lymphoma with brentuximab vedotin

TO THE EDITOR: [Abstract] The treatment outcome of relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma (ENKL) is poor. Brentuximab vedotin, an anti-CD30 antibody-drug conjugate, has recently been approved for the treatment of relapsed Hodgkin's lymphoma and anaplastic large-cell lymphoma (ALCL). We report on a case of a 63-year-old man who presented with multiple skin lesions, and was diagnosed with ENKL. Since the disease was refractory to most chemotherapy drugs, we performed an analysis of the skin biopsy to evaluate marker CD30. The patient's lymphoma cells demonstrated CD30-positivity, and treatment with single-agent brentuximab vedotin was commenced as of December 2013. Following 4 cycles of single-agent brentuximab vedotin treatment, all of the skin lesions had cleared, and a [18F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scan demonstrated complete remission (CR) of the disease. This study suggests that single-agent brentuximab vedotin could be effective in the treatment of CD30-positive non-Hodgkin lymphomas other than ALCL. Extranodal natural killer (NK)/T-cell lymphoma (ENKL) is an aggressive, non-Hodgkin lymphoma for which a standard therapy has not yet been established. The treatment outcomes of advanced relapsed or refractory ENKL, with conventional chemotherapy, are extremely poor [1]. Brentuximab vedotin (Seattle Genetics Inc., Bothell, WA, USA) is an anti-CD30 antibody-drug conjugate that is covalently linked, via a protease-cleavable linker, to the microtubule-disrupting agent, monomethyl auristatin E. In a phase 1 clinical trial of 45 patients with relapsed or refractory CD30-positive lymphomas, treatment with single-agent brentuximab vedotin resulted in an overall response rate (ORR) of 67% [2]. In a phase 2 clinical trial for relapsed or refractory systemic anaplastic large-cell lymphoma (ALCL), single-agent brentuximab vedotin treatment resulted in an ORR of 86%, and a complete remission (CR) rate of 57% [3]. Based on these results, brentuximab vedotin was approved by the United States Food and Drug Administration, in August 2011, for the treatment of relapsed Hodgkin's lymphoma and ALCL. In a recent phase 2 clinical trial for relapsed T-cell lymphoma, treatment with single-agent brentuximab vedotin resulted in an ORR of 41% in relapsed T-cell lymphoma and 54% in angioimmunoblastic T-cell lymphoma patients, respectively [4]. Therefore, these studies demonstrate that single-agent brentuximab vedotin treatment in non-Hodgkin lymphoma patients with tumors expressing CD30 can induce objective responses. Here, we report on a case of a 63-year-old man with refractory CD30-positive ENKL in which CR was achieved with single-agent brentuximab vedotin treatment.

Brentuximab vedotin in patients aged 60 years or older with relapsed or refractory CD30-positive lymphomas: a retrospective evaluation of safety and efficacy

Older adults constitute a significant proportion of the cancer population, but are underrepresented in clinical trials. We conducted a retrospective analysis of the safety and efficacy of brentuximab vedotin in adults ≥ 60 years with relapsed CD30-positive lymphomas. Baseline characteristics and safety data were compared for older (median age 66) and younger patients (< 60 years, median age 32). Exposure to brentuximab vedotin was comparable. Older patients had more preexisting conditions (median 11 vs. 6) and were receiving more concomitant medications (median 7.5 vs. 4). Higher rates of anemia (30% vs. 10%), peripheral sensory neuropathy (60% vs. 46%), fatigue (58% vs. 43%) and adverse events ≥ grade 3 (70% vs. 56%) occurred in older patients. Objective response rates were 56% and 100% in older patients with Hodgkin lymphoma and systemic anaplastic large cell lymphoma, respectively. With appropriate monitoring, brentuximab vedotin may represent a meaningful clinical option for older patients with relapsed CD30-positive lymphomas.

Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin's Lymphoma

Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E, an antimicrotubule agent, into CD30-expressing cells. In phase I studies, brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory CD30-positive lymphomas. In this multinational, open-label, phase II study, the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin's lymphoma (HL) after autologous stem-cell transplantation (auto-SCT). Patients had histologically documented CD30-positive HL by central pathology review. A total of 102 patients were treated with brentuximab vedotin 1.8 mg/kg by intravenous infusion every 3 weeks. In the absence of disease progression or prohibitive toxicity, patients received a maximum of 16 cycles. The primary end point was the overall objective response rate (ORR) determined by an independent radiology review facility. The ORR was 75% with complete remission (CR) in 34% of patients. The median progression-free survival time for all patients was 5.6 months, and the median duration of response for those in CR was 20.5 months. After a median observation time of more than 1.5 years, 31 patients were alive and free of documented progressive disease. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75% of patients with relapsed or refractory HL after auto-SCT. Durable CRs approaching 2 years were observed, supporting study in earlier lines of therapy.

Brentuximab Vedotin: A New Age in the Treatment of Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma

To review the clinical trial data, pharmacology, pharmacokinetics, and adverse effects of brentuximab vedotin. A literature search was performed using MEDLINE and PubMed (both 1966-October 2011), as well as the American Society of Hematology abstracts (2000-January 2012), using the primary search terms brentuximab vedotin, SGN-35, Hodgkin lymphoma (HL), and anaplastic large cell lymphoma (ALCL). Published and ongoing clinical studies and abstracts in the English language that detail the pharmacology, pharmacokinetics, safety, and clinical efficacy of brentuximab vedotin in the treatment of HL and ALCL were included in this review. Brentuximab vedotin is an antibody drug conjugate that combines the anti-CD30 antibody, cAC10, with the synthetic tubulin disrupting agent monomethyl auristatin E. A Phase 1 trial in patients with relapsed and refractory HL or systemic ALCL supported a dose of 1.8 mg/kg every 3 weeks. The drug was well tolerated, with the majority of adverse reactions being grade 1 or 2 in severity. Common toxicities included fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy. Phase 2 studies in the same patient populations illustrated objective response rates of 73-86% with an acceptable toxicity profile. Based on results of these Phase 2 trials, the Food and Drug Administration granted approval of brentuximab vedotin in August 2011 for the treatment of relapsed and refractory HL or ALCL. Phase 1 and 2 clinical trial data indicate that brentuximab vedotin is efficacious and safe in patients with relapsed and refractory CD30-positive lymphomas. This agent is being investigated in combination with chemotherapy to further elucidate its role in lymphoma therapy.

Brentuximab Vedotin (SGN-35) for Relapsed CD30-Positive Lymphomas

Hodgkin's lymphoma and anaplastic large-cell lymphoma are the two most common tumors expressing CD30. Previous attempts to target the CD30 antigen with monoclonal-based therapies have shown minimal activity. To enhance the antitumor activity of CD30-directed therapy, the antitubulin agent monomethyl auristatin E (MMAE) was attached to a CD30-specific monoclonal antibody by an enzyme-cleavable linker, producing the antibody-drug conjugate brentuximab vedotin (SGN-35). In this phase 1, open-label, multicenter dose-escalation study, we administered brentuximab vedotin (at a dose of 0.1 to 3.6 mg per kilogram of body weight) every 3 weeks to 45 patients with relapsed or refractory CD30-positive hematologic cancers, primarily Hodgkin's lymphoma and anaplastic large-cell lymphoma. Patients had received a median of three previous chemotherapy regimens (range, one to seven), and 73% had undergone autologous stem-cell transplantation. The maximum tolerated dose was 1.8 mg per kilogram, administered every 3 weeks. Objective responses, including 11 complete remissions, were observed in 17 patients. Of 12 patients who received the 1.8-mg-per-kilogram dose, 6 (50%) had an objective response. The median duration of response was at least 9.7 months. Tumor regression was observed in 36 of 42 patients who could be evaluated (86%). The most common adverse events were fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy. Brentuximab vedotin induced durable objective responses and resulted in tumor regression for most patients with relapsed or refractory CD30-positive lymphomas in this phase 1 study. Treatment was associated primarily with grade 1 or 2 (mild-to-moderate) toxic effects. (Funded by Seattle Genetics; ClinicalTrials.gov number, NCT00430846.).

The Antibody-Drug Conjugate Brentuximab Vedotin (SGN-35) Induced Multiple Objective Responses in Patients with Relapsed or Refractory CD30-Positive Lymphomas in a Phase 1 Weekly Dosing Study.

Abstract 2731Poster Board II-707 Background:The antibody-drug conjugate (ADC) brentuximab vedotin (SGN-35) delivers the antitubulin agent monomethyl auristatin E (MMAE) to CD30-positive malignant cells by binding specifically to CD30 on the cell surface and releasing MMAE inside the cell via lysosomal degradation. In a previous phase 1 study with every 3 week dosing, 54% of patients achieved an objective response (CR/PR) at brentuximab vedotin doses ≥1.2 mg/kg [ASH 2008 abstract 1006]. Methods:To investigate the tolerability and antitumor activity of a more frequent dosing regimen, a multicenter phase 1 study was conducted in patients with refractory or recurrent CD30-positive lymphomas using a 3 + 3 dose-escalation design. Brentuximab vedotin was administered weekly for 3 weeks in 28-day treatment cycles at doses of 0.4 to 1.4 mg/kg (30-min or 2-hr IV infusions). Patients with stable disease or better (Cheson 2007) after two cycles were eligible to receive additional brentuximab vedotin treatment cycles. Results:A total of 37 patients, 31 with Hodgkin lymphoma (HL), 5 with systemic anaplastic large cell lymphoma (ALCL), and 1 with peripheral T-cell lymphoma, were enrolled and treated. Median age was 35 (range 13–82) and most patients (89%) had an ECOG performance status of 0/1. Patients received a median of 3 prior chemotherapy regimens (range 1–8); 62% previously received an autologous stem cell transplant. More than 50% of patients (21 of 37) had disease that did not respond to their most recent prior therapy. Dose-limiting toxicities included G3 diarrhea, G3 vomiting, and G4 hyperglycemia. The maximum tolerated dose was exceeded at 1.4 mg/kg. The most common treatment-related adverse events were peripheral neuropathy, nausea, fatigue, diarrhea, dizziness, and neutropenia; most were grade 1 or 2 in severity. Exposure to brentuximab vedotin (AUC) increased relative to dose level. Among efficacy evaluable patients across all dose levels, the objective response rate (ORR) was 46% (16 of 35), with 29% of patients (10 of 35) attaining a complete remission. Median duration of response to date is at least 16 weeks (range, 0.1+ to 34+); 15 patients continue on treatment. Conclusions:Weekly dosing with brentuximab vedotin was generally well tolerated and induced a high rate of objective responses in heavily pretreated patients with HL and systemic ALCL. A pivotal trial of this ADC in patients with relapsed or refractory HL has completed enrollment. Disclosures:Fanale:Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is an investigational agent. Bartlett:Seattle Genetics, Inc.: Research Funding. Forero-Torres:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Horning:Seattle Genetics, Inc.: Research Funding. Franklin:Seattle Genetics, Inc.: Research Funding. Lynch:Seattle Genetics, Inc.: Employment. Sievers:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment.