Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dose (FD)/gemcitabine 1000 mg/m was the highest dose level tested. Dose-limiting toxicities (DLTs) were mostly hematological and resulted in the expansion of a lower dose level (PM01183 3.5 mg FD/gemcitabine 800 mg/m); 19 patients at this dose level were evaluable but >30% had DLT and >20% had febrile neutropenia. No DLT was observed in 11 patients treated at PM01183 3.0 mg FD/gemcitabine 800 mg/m, which was defined as the RD. This regimen was feasible and tolerable with manageable toxicity; mainly grade 3/4 myelosuppression. Non-hematological toxicity comprised fatigue, nausea, vomiting, and transaminases increases. Fifteen (33%) patients received ≥6 cycles with no cumulative hematological toxicity. Pharmacokinetic analysis showed no evidence of drug-drug interaction. Nine of 38 patients had response as per RECIST (complete [3%] and partial [21%]), for an overall response rate (ORR) of 24% (95% Confidence Interval [CI] 12-40%). Eleven patients (29%) had disease stabilization ≥4 months. Responses were durable (median of 8.5 months): overall median progression-free survival (PFS) was 4.2 months (95% CI, 2.7-6.5 months). Conclusions The RD for this combination is PM01183 3.0 mg FD (or 1.6 mg/m)/gemcitabine 800 mg/m d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types.

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7544 Background: GA201, a humanized, engineered IgG1 anti-Epidermal Growth Factor Receptor (EGFR) mAb designed to enhance ADCC, has shown promising clinical activity in phase I and in the neoadjuvant treatment of head and neck cancer. This phase Ib study (NCT01185847) aimed to determine the safety, pharmacokinetics (PK), activity and recommended phase II dose (RP2D) of GA201 in combination with chemotherapy in non-squamous NSCLC. Methods: Successive cohorts received GA201 1000 mg or 1400 mg (IV d1, d8 then 2-weekly (q2W)) in combination with chemotherapy at standard doses. Data cut off was 7 months after enrolling the last patient. Results: 14 patients (4 female) with performance status 0-1 were enrolled. No maximum tolerated dose was reached. Most common adverse events (AEs – all grades) included rash (100%), hypomagnesaemia (71%), infusion-related reactions (64%), mucosal inflammation (57%) and anemia (50%). AEs of ≥ grade 3 included rash (71%), skin fissure (21%), dry skin (14%), paronychia (14%), and asthenia (14%). Median timeto improvement of rash grade 3 was 11 days. AEs led to dose reduction for 4 patients and discontinuation for 1 patient. There were 6 confirmed partial responses (43%, 5 in 1400 mg cohort) and 7 patients (50%) with stable disease >=9 weeks. Duration of response ranged between 5 and 42 weeks (3 patients still ongoing). Preliminary biomarker analysis shows a correlation between tumor-infiltrating CD16+ immune cells and target lesion shrinkage at first tumor assessment [R(spear)=-0.65 (p=0.02)]; no apparent correlation between EGFR H-score and response was found. PK data supports 1400 mg as the RP2D (d1, d8 then q2W). Conclusions: The RP2D of GA201 in combination with chemotherapy was established to be 1400 mg. The incidence of EGFR associated rash was high and guidelines to reduce its severity were implemented with a noted improvement in tolerability. Promising antitumor activity was observed. Biomarker data support the mode of action of GA201 via ADCC. A randomized phase II trial of this combination is ongoing and fully recruited.

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