A phase 1, dose-escalation study of PF-06664178, an anti-Trop-2/Aur0101 antibody-drug conjugate in patients with advanced or metastatic solid tumors

8500 Background: A defining feature of HL and sALCL is CD30 expression on malignant cells. The ADC SGN-35 comprises an anti-CD30 antibody conjugated to the antitubulin agent monomethyl auristatin E (MMAE). SGN-35 causes cell cycle arrest and apoptosis by binding to CD30 on the tumor cell surface, internalizing, and releasing MMAE into the cell. In a previous phase 1 study with q3 wk dosing, 54% of pts achieved an objective response (CR/PR) at SGN-35 doses ≥1.2 mg/kg [ASH 2008 abstract 1006]. Methods: To assess if more frequent dosing might maximize anti-tumor activity with acceptable tolerability, a multicenter, phase 1, weekly dosing, dose-escalation study (3+3 design) was conducted in pts with refractory or recurrent HL or sALCL. SGN-35 was administered weekly at doses of 0.4–1 mg/kg (2-hr IV infusions). Pts with stable disease or better (Cheson 2007) after two 28-day cycles (6 doses) were eligible to continue SGN-35 treatment. Results: In 17 pts, median age was 38 yrs (range 25–67). Pts received a median of 4 prior therapies; 65% received an autologous SCT. MTD has not been defined. One related G3 event (diarrhea) and no related G4 events occurred. The most common related adverse events were G1/G2 rash, nausea, and peripheral neuropathy. Exposure to SGN-35 (AUC) increased relative to dose level. Multiple CRs were observed at higher doses ( table ); observed time to response in the 1 mg/kg dose group was approximately 8 wks. The 7 pts with CRs all remain on treatment. Enrollment to SGN-35 monotherapy continues at 1.2 mg/kg; combination therapy will be subsequently explored. Conclusions: SGN-35 was generally well tolerated and induced CRs in 7 of 8 evaluable pts at the two highest doses in heavily pretreated patients. Pivotal trials of this antibody-drug conjugate will initiate in early 2009. [Table: see text] [Table: see text]

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Preliminary results from a phase 1 study of the antibody-drug conjugate ABBV-221 in patients with solid tumors likely to express EGFR.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.2510 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 2510-2510 ◽

Cited By ~ 9

Author(s):

Emiliano Calvo ◽

James M. Cleary ◽

Victor Moreno ◽

Maryella Gifford ◽

Lisa Roberts-Rapp ◽

...

Keyword(s):

Solid Tumors ◽

Dose Escalation ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Mitigation Strategies ◽

Antibody Drug Conjugate ◽

Drug Conjugate ◽

Egfr Ligand ◽

Infusion Reactions ◽

Antibody Drug

2510 Background: ABBV-221 is a 2nd-generation antibody-drug conjugate (ADC) targeting EGFR based on the 1st-generation ADC ABT-414. ABT-414 shows efficacy in glioblastoma (GBM) patients (pts) with EGFR amplification in ongoing studies. ABBV-221 is an affinity matured monoclonal antibody against EGFR linked to the toxin MMAE. ABBV-221 has higher affinity for overexpressed EGFR than ABT-414, potentially allowing it to target a broader range of tumor types. Methods: This is a Phase 1, multicenter study to determine maximum tolerated dose (MTD) and recommended Phase 2 dose (RPTD) of ABBV-221. Pts are required to have an EGFR-dependent cancer to be eligible. Starting dose of ABBV-221: 0.3 mg/kg IV infused over 3 hrs for each 21-day cycle, with alternate dosing schedules utilized (2 wks on, 1 wk off or weekly) to mitigate infusion reactions. Results: As of 11 January 2017, 42 pts were treated (13 colon, 5 head & neck (H&N) cancer, 5 non-small cell lung cancer, 5 GBM, 2 breast, 12 other). Ten dose escalation cohorts have been completed with the last cleared dose 4.5 mg/kg per cycle. Tumor tissue samples were evaluated for EGFR protein expression by IHC, EGFR and EGFR ligand mRNA expression by RNAseq, and the results compared to outcome. The most common adverse event (AE) was infusion reaction in 18/42 pts (43%); 3 pts experienced severe infusion reactions. Several mitigation strategies were used to permit continued dose escalation. The other most common AE was fatigue in 17/42 pts (41%). Only 1 pt had keratitis (Grade 4). Sixteen pts (38%) had stable disease (SD), including 4 pts who remained on study longer than 6 months. One H&N pt who has received 2 cycles of ABBV-221 had an unconfirmed partial response and continues to be treated. This pt had high levels of both EGFR and EGFR ligand. Preliminary pharmacokinetics (PK) analysis suggests ABBV-221 exposures are approximately dose-proportional. Conclusions: Safety, PK, pharmacodynamics, and preliminary efficacy data of ABBV-221 warrant further study in this population. Infusion reactions have been manageable and primarily a first dose phenomenon. The duration of SD in pts with refractory solid tumors is encouraging. Clinical trial information: NCT02365662.

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