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To determine the safety, pharmacokinetics, and recommended phase II dose of an antibody-drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC). Two phase I studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma-derived AGS-16M8F and Chinese hamster ovary-derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kg until unacceptable toxicity or progression. The study was terminated before reaching the MTD. A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks. The AGS-16M8F study ( = 26) closed before reaching the MTD. The median duration of treatment was 12 weeks (1.7-83 weeks). One subject had durable partial response (PR; 83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study ( = 34), the protocol-defined MTD was 3.6 mg/kg, but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose deescalations. The 1.8 mg/kg dose was determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range, 100-143 weeks). Eight subjects at 2.7 mg/kg and 1.8 mg/kg had disease control >37 weeks (37.5-141 weeks). AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks. .

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Twenty-eight patients with advanced measurable gastric carcinoma were treated with leucovorin (dl-CF; folinic acid; dl-5-formyltetrahydrofolic acid) 500 mg/m2 administered as a two-hour infusion and 5-fluorouracil (5-FU) 600 mg/m2 intravenous (IV) push midinfusion. Treatment was administered weekly for 6 weeks followed by a 2-week rest. Twenty-five patients were evaluable for response. Twelve of them had received previous combination chemotherapy that included 5-FU. Median age was 59 years, and median Eastern Cooperative Oncology Group (ECOG) performance status was 2. Three patients had partial responses and two of them had been treated previously with 5-FU. Twelve patients had stable disease. Five of these patients had subjective improvement with improved performance status and/or decreased dysphagia. The 95% confidence interval for response is 3% to 32%. Median survival time for all 28 patients enrolled in the study was 22 weeks. Toxicity was moderate and consisted primarily of diarrhea. Myelosuppression, skin rash, and increased lacrimation also occurred. Plasma concentrations of the active reduced folates, I-CF and 5-methyltetrahydrofolic acid (5-CH3FH4), were greater than the 10 mumol/L levels that potentiate 5-FU activity in in vitro models, for more than four hours in all five patients in whom pharmacokinetics were studied. 5-FU and high-dose dl-CF has activity in patients with gastric carcinoma including patients who had previously progressed on 5-FU-containing combinations. Further study in a larger patient population is necessary to determine the usefulness of this regimen in gastric carcinoma.

Introduction: CD19 expression has been demonstrated in many types of NHL, including FL and DLBCL. Pyrrolobenzodiazepine (PBD) is a DNA cross-linking agent. ADCT-402, a humanized antibody directed against human CD19 conjugated to a PBD dimer toxin, has demonstrated potent pre-clinical anti-tumor activity against CD19-expressing B-cell malignancies. Interim results of the first in-human clinical study of ADCT-402 in the difficult-to-treat relapsed/refractory NHL setting are reported here. Methods: Patients (pts) with recurrent B-cell NHL who had failed or were intolerant to established therapies, or had no other treatment options available, were assigned IV infusions of ADCT-402 every 3 weeks (1 cycle) according to a 3 + 3 dose-escalation study design. No intra-patient dose escalation was allowed. Safety, tolerability, and efficacy were assessed. Results: As of 3 Feb 2017, 37 pts (23 male, 14 female; median age: 69 years [range 24-85]; median number of previous therapies: 3 [range 1-10]) have been recruited. Diagnoses included DLBCL (n = 22), MCL (n = 7), FL (n = 6) and other B-cell NHL (n = 2). Pts received ADCT-402 doses ranging from 15 to 200 μg/kg (median cycles: 3 [range 1-11]). Treatment-emergent adverse events (TEAEs) included fatigue (21 [56.8%] pts), peripheral edema (10 [27.0%] pts), and nausea (9 [24.3%] pts). Grade ≥ 3 TEAEs included decreased ABSTRACT 49