A phase 2, open-label study of brentuximab vedotin in patients with CD30-expressing solid tumors.

Purpose Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate used in the treatment of several types of lymphomas. Expression of the target antigen has also been reported on a variety of malignant tumors of nonlymphoid origin. This phase 2, open-label study evaluated the safety and antitumor activity of BV in patients with CD30-expressing nonlymphomatous malignancies. Methods Patients were dosed with 1.8 or 2.4 mg/kg BV once every three weeks. Antitumor activity was assessed at Cycles 2, 4, and every 4 cycles thereafter. Patients with stable disease or better were eligible to continue treatment until disease progression, unacceptable toxicity, or study closure. Results Of the 2693 patients screened, 3.8% had solid tumors with CD30 expression and 63 eligible patients with solid tumors enrolled in this study. The most common CD30 positive solid tumors were testicular cancer and mesothelioma. Both subtypes had more than one patient with an objective response. The median duration of BV exposure was 6.1 weeks. The disease control rate, defined as achieving stable disease or better at any point during the study, was 55%. The objective response rate was 11%, with a median duration of response of 2.92 months. The most common adverse events reported were fatigue (57%), nausea (33%), and decreased appetite (32%). Conclusion The safety profile of BV in patients with solid tumors was similar to the known safety profile of BV. In solid tumors, BV had modest activity as a single agent, which was similar to other second-line treatments already available to patients.

A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers.

Purpose ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, a novel cell surface target expressed on most pancreatic and gastric cancers. This first-in-human study of ASG-5ME evaluated safety, pharmacokinetics, and preliminary activity of ASG-5ME in advanced pancreatic and gastric cancer patients. Experimental Design This phase 1, dose-escalation, multicenter study determined the maximum tolerated dose (MTD) and assessed safety and antitumor activity. The dose-escalation portion enrolled metastatic pancreatic adenocarcinoma patients; gastric adenocarcinoma patients were included in the dose-expansion portion. Patients received ASG-5ME intravenously on Days 1, 8, and 15 of 28-day cycles. Results Thirty-five pancreatic cancer patients (median age 63 years; performance status 0 [40 %] or 1 [60 %]) were treated at doses of 0.3 to 1.5 mg/kg (median duration 8.1 weeks). The MTD was exceeded at 1.5 mg/kg (n = 7) with 1 dose-limiting toxicity (DLT) of Grade 4 gastrointestinal hemorrhage. Four patients experienced non-DLT Grade 3 or 4 neutropenia. Fifteen gastric cancer patients (median age 59 years; performance status 0 [33 %] or 1 [67 %]) were treated at the identified MTD of 1.2 mg/kg (median duration 8.7 weeks). Common drug-related adverse events included fatigue (29 %), nausea (23 %), and vomiting (23 %) for pancreatic cancer patients and fatigue (33 %) and decreased appetite (33 %) for gastric cancer patients. Best clinical response was 1 partial response in each cohort. Disease-control rates of 33 % (pancreatic) and 47 % (gastric) were observed at the MTD. All patient biopsies (23 pancreatic, 15 gastric) expressed the SLC44A4 antigen. Conclusions ASG-5ME treatment was generally well tolerated with limited evidence of antitumor activity.

Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma.

PURPOSE: This first-in-human study evaluated the CD70-targeted antibody-drug conjugate SGN-75 in patients with relapsed or refractory CD70-positive non-Hodgkin lymphoma (NHL) or metastatic renal cell carcinoma (RCC). Methods SGN-75 was administered intravenously to 58 patients (39 RCC, 19 NHL) every 3 weeks (Q3Wk; doses escalated from 0.3 to 4.5 mg/kg) or on Days 1, 8, and 15 of 28-day cycles (weekly; doses of 0.3 or 0.6 mg/kg). Dose-limiting toxicities were evaluated during Cycle 1; treatment response was monitored every 2 cycles. RESULTS: The maximum tolerated dose of SGN-75 in RCC patients was 3 mg/kg Q3Wk. Due to toxicity concerns (idiopathic thrombocytopenic purpura in 2 NHL patients treated weekly), dose escalation in the weekly schedule was terminated; no regimen was recommended for NHL patients. The most common adverse events reported in patients treated Q3Wk (N = 47) were fatigue (40%), dry eye (32%), nausea (30%), and thrombocytopenia (26%). The nadir for thrombocytopenia typically occurred during Cycle 1. Ocular adverse events (e.g., corneal epitheliopathy, dry eye) were reported for 57% of patients treated Q3Wk and were generally reversible. Antitumor activity in patients treated Q3Wk included 1 complete response, 2 partial responses, and 20 stable disease. SGN-75 exposures were approximately dose proportional, with a mean terminal half-life of 10 days. Substantial depletions of CD70-positive peripheral blood lymphocytes were observed after SGN-75 treatment. CONCLUSIONS: Modest single-agent activity and generally manageable adverse events were observed in heavily pretreated RCC and NHL patients. Administration Q3Wk was better tolerated than weekly dosing. Targeted ablation of CD70-positive lymphocytes was demonstrated.

A phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma.

This first-in-human, phase I study evaluated the safety, maximum-tolerated dose, pharmacokinetics, and antitumor activity of dacetuzumab in 44 patients with advanced multiple myeloma. Patients received intravenous dacetuzumab, either in 4 uniform weekly doses (first 4 cohorts) or using a 5-week intrapatient dose escalation schedule (7 subsequent cohorts; the last 3 cohorts received steroid pre-medication). An initial dose of 4 mg/kg dacetuzumab exceeded the maximum-tolerated dose for uniform weekly dosing. Intrapatient dose escalation with steroid pre-medication appeared effective in reducing symptoms of cytokine release syndrome and the maximum-tolerated dose with this dosing schema was 12 mg/kg/week. Adverse events potentially related to dacetuzumab included cytokine release syndrome symptoms, non-infectious ocular inflammation, and elevated hepatic enzymes. Peak dacetuzumab blood levels increased with dose. Nine patients (20%) had a best clinical response of stable disease. The observed safety profile suggested that dacetuzumab may be combined with other multiple myeloma therapies. Two combination trials are ongoing. Clinical trials gov identifier: NCT00079716.

SGN-LIV1A: a novel antibody-drug conjugate targeting LIV-1 for the treatment of metastatic breast cancer.

In this article, we describe a novel antibody-drug conjugate (ADC; SGN-LIV1A), targeting the zinc transporter LIV-1 (SLC39A6) for the treatment of metastatic breast cancer. LIV-1 was previously known to be expressed by estrogen receptor-positive breast cancers. In this study, we show that LIV-1 expression is maintained after hormonal therapy in primary and metastatic sites and is also upregulated in triple-negative breast cancers. In addition to breast cancer, other indications showing LIV-1 expression include melanoma, prostate, ovarian, and uterine cancer. SGN-LIV1A consists of a humanized antibody conjugated through a proteolytically cleavable linker to monomethyl auristatin E, a potent microtubule-disrupting agent. When bound to surface-expressed LIV-1 on immortalized cell lines, this ADC is internalized and traffics to the lysozome. SGN-LIV1A displays specific in vitro cytotoxic activity against LIV-1-expressing cancer cells. In vitro results are recapitulated in vivo where antitumor activity is demonstrated in tumor models of breast and cervical cancer lineages. These results support the clinical evaluation of SGN-LIV1A as a novel therapeutic agent for patients with LIV-1-expressing cancer.

A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors.

BACKGROUND: Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms including DLBCL and is a potential target for immunotherapy. Dacetuzumab (SGN-40), a non-blocking, partial agonist, humanized IgG1, anti-CD40 monoclonal antibody, has previously demonstrated anti-lymphoma activity in a phase I study. METHODS: A phase II study was undertaken to evaluate the rate and duration of objective responses and safety of single-agent dacetuzumab in relapsed DLBCL. Forty-six adult patients with relapsed/refractory DLBCL received up to 12 cycles of intravenous dacetuzumab using intrapatient dose-escalation to a target dose of 8 mg/kg/week in an initial 5-week cycle, followed by 4-week cycles of 8 mg/kg/week. Study endpoints included rate and duration of objective responses, safety, survival, pharmacokinetics, immunogenicity, and exploratory correlative studies. RESULTS: Overall response rate was 9% and disease control rate (complete remission + partial remission + stable disease) was 37%. Common non-hematologic adverse events (AEs) included fatigue, headache, chills, fever, and nausea. The most frequent Grade 3-4 non-hematologic AE was deep venous thrombosis (3 patients). Grade 3-4 lymphopenia (41%), neutropenia (13%), or thrombocytopenia (19%) occurred without associated infection or bleeding. Reversible ocular events, including conjunctivitis and ocular hyperemia, occurred in 8 patients (17%). Patient-specific factors, including Fc-gamma-RIIIa polymorphism, did not appear to correlate with antitumor activity. CONCLUSIONS: Single-agent dacetuzumab has modest activity and manageable toxicity in unselected patients with relapsed DLBCL. Combination regimens and robust methods of patient selection may be necessary for further development. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00435916.

Pilot study of dacetuzumab in combination with rituximab and gemcitabine for relapsed or refractory diffuse large B-cell lymphoma.

Dacetuzumab, a CD40-targeted, humanized antibody, mediates antitumor activity through effector cell functions and direct apoptotic signal transduction. Preclinical studies demonstrated synergistic activity between dacetuzumab, gemcitabine and rituximab against non-Hodgkin lymphoma in vivo. A phase 1b safety/efficacy study of dacetuzumab in combination with rituximab and gemcitabine was conducted in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients received dacetuzumab at doses of 8 or 12 mg/kg IV weekly with rituximab (375 mg/m(2) IV weekly in cycle 1, then every 28 days) and gemcitabine (1000 mg/m(2) IV, days 1, 8 and 15, or days 1 and 15). Thirty-three patients with a median age of 67 years were enrolled. Common adverse events (≥ 15%) were grade 1/2 cytokine release syndrome, nausea, fatigue, thrombocytopenia, headache, decreased appetite, dyspnea, neutropenia, pyrexia, anemia, diarrhea, edema, constipation and cough. Dacetuzumab-related grade 3/4 adverse events occurred infrequently. Six of 30 evaluable patients achieved a complete response (CR) and eight a partial response (PR) per investigator assessment for an overall response rate (ORR) of 47%.

CD40 pathway activation status predicts response to CD40 therapy in diffuse large B cell lymphoma.

The primary function of B cells, critical components of the adaptive immune response, is to produce antibodies against foreign antigens, as well as to perform isotype class switching, which changes the heavy chain of an antibody so that it can interact with different repertoires of effector cells. CD40 is a member of the tumor necrosis factor superfamily of cell surface receptors that transmits survival signals to B cells. In contrast, in B cell cancers, stimulation of CD40 signaling results in a heterogeneous response in which cells can sometimes undergo cell death in response to treatment, depending on the system studied. We found an association between sensitivity to CD40 stimulation and mutation of the tumor suppressor p53 in a panel of non-Hodgkin's lymphoma cell lines. Consistent with p53's tumor suppressor role, we found that higher levels of intrinsic DNA damage and increased proliferation rates, as well as higher levels of BCL6, a transcriptional repressor proto-oncogene, were associated with sensitivity to CD40 stimulation. In addition, CD40 treatment-resistant cell lines were sensitized to CD40 stimulation after the introduction of DNA-damaging agents. Using gene expression analysis, we also showed that resistant cell lines exhibited a preexisting activated CD40 pathway and that an mRNA expression signature comprising CD40 target genes predicted sensitivity and resistance to CD40-activating agents in cell lines and mouse xenograft models. Finally, the gene signature predicted tumor shrinkage and progression-free survival in patients with diffuse large B cell lymphoma treated with dacetuzumab, a monoclonal antibody with partial CD40 agonist activity. These data show that CD40 pathway activation status may be useful in predicting the antitumor activity of CD40-stimulating therapeutic drugs.

Phase I study of the humanized anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkin's lymphoma.

PURPOSE: To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics, and antitumor activity of dacetuzumab in patients with refractory or recurrent B-cell non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: In this open-label, dose-escalation phase I study, dacetuzumab was administered to six cohorts of adult patients. In the first cohort, patients received 2 mg/kg weekly for 4 weeks; in all other cohorts, an intrapatient dose-escalation schedule was used with increasing doses up to a maximum of 8 mg/kg. Patients with clinical benefit after one cycle of dacetuzumab were eligible for a second cycle. RESULTS: In the 50 patients who received dacetuzumab, no dose dependence of adverse events (AEs) was observed. The most common AEs in >or= 20% of patients were fatigue, pyrexia, and headache; most were grade 1 or 2. Noninfectious inflammatory eye disorders occurred in 12% of patients. AEs grade >or= 3 occurred in 30% of patients and included disease progression, anemia, pleural effusion, and thrombocytopenia. Most laboratory abnormalities were grade 1 or 2; transient elevated hepatic aminotransferases occurred in 52% of patients. Two patients experienced dose-limiting toxicity: grade 3 conjunctivitis and transient vision loss in cohort (1), and grade 3 ALT elevation in cohort IV. The MTD of dacetuzumab was not established at the dose levels tested. Six objective responses were reported (one complete response, five partial responses). Tumor size decreased in approximately one third of patients. CONCLUSION: Dacetuzumab monotherapy was well tolerated in patients with NHL in doses up to 8 mg/kg/wk. Preliminary response data are encouraging and support additional studies of dacetuzumab in this patient population.