Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors

Abstract

Purpose Our preclinical work identified depletion of ATR as a top candidate for topoisomerase 1 (TOP1) inhibitor synthetic lethality and showed that ATR inhibition sensitizes tumors to TOP1 inhibitors. We hypothesized that a combination of selective ATR inhibitor M6620 (previously VX-970) and topotecan, a selective TOP1 inhibitor, would be tolerable and active, particularly in tumors with high replicative stress. Patients and Methods This phase I study tested the combination of M6620 and topotecan in 3-week cycles using 3 + 3 dose escalation. The primary end point was the identification of the maximum tolerated dose of the combination. Efficacy and pharmacodynamics were secondary end points. Results Between September 2016 and February 2017, 21 patients enrolled. The combination was well tolerated, which allowed for dose escalation to the highest planned dose level (topotecan 1.25 mg/m², days 1 to 5; M6620 210 mg/m², days 2 and 5). One of six patients at this dose level experienced grade 4 thrombocytopenia that required transfusion, a dose-limiting toxicity. Most common treatment-related grade 3 or 4 toxicities were anemia, leukopenia, and neutropenia (19% each); lymphopenia (14%); and thrombocytopenia (10%). Two partial responses (≥ 18 months, ≥ 7 months) and seven stable disease responses ≥ 3 months (median, 9 months; range, 3 to 12 months) were seen. Three of five patients with small-cell lung cancer, all of whom had platinum-refractory disease, had a partial response or prolonged stable disease (10, ≥ 6, and ≥ 7 months). Pharmacodynamic studies showed preliminary evidence of ATR inhibition and enhanced DNA double-stranded breaks in response to the combination. Conclusion To our knowledge, this report is the first of an ATR inhibitor-chemotherapy combination. The maximum dose of topotecan plus M6620 is tolerable. The combination seems particularly active in platinum-refractory small-cell lung cancer, which tends not to respond to topotecan alone. Phase II studies with biomarker evaluation are ongoing.

Trial registration: ClinicalTrials.gov NCT02487095.

Fig 1.

Trial schema and dose escalation schedule. IV, intravenously.

Fig 2.

Efficacy in the overall population. (A) The waterfall plot shows responses in evaluable patients (n = 19). (B) Computed tomography scans from before and 6 weeks after treatment that show a partial response; area of tumor indicated by circle and (C) CA-125 trend in a patient with previously treated endometrial cancer. (D) The swimmer plot shows responses and durations of response in evaluable patients. (*) Patient came off treatment because of brain metastases. DL, dose level; HGNEC, high-grade neuroendocrine cancer; NSCLC, non–small-cell lung cancer; SCLC, small-cell lung cancer.

Fig 3.

Tumor responses in patients with refractory small-cell lung cancer (SCLC). (A) Computed tomography (CT) scans from before treatment and at 5 months after treatment show partial response in a patient with refractory SCLC, with a striking decrease in size and number of splenic metastases accompanied by a marked decrease in metabolic activity of the lesions, which is ongoing at 7 months. (B) CT scans from before treatment and 6 months after treatment that show regression of a left-sided adrenal metastasis in a patient with refractory SCLC. Best tumor response in this patient was stable disease (−25% decrease in sum of target lesions), and the patient continues with treatment at 6 months. (C) CT scans from before and 9 months after treatment that show a stable subcarinal lymph node in a patient with refractory SCLC. Best tumor response in this patient was stable disease (−26% decrease in sum of target lesions). This patient continued with treatment for 10 months and discontinued because of brain metastases. Tumor areas are indicated by arrows.

Fig 4.

Pharmacodynamic assessment of γH2AX formation in plucked hair bulbs and peripheral blood mononuclear cells (PBMCs) after topotecan and M6620. (A) Diagram depicting the collection of PBMCs and hair follicles. All patients received topotecan on days 1, 2, and 3, with patients 7 to 21 receiving M6620 on day 2. Samples were collected before infusions of topotecan and M6620 (D1-pre), 5 to 30 minutes after day 2 topotecan (D2-post 1), 30 minutes to 1 hour after day 2 M6620 (D2-post 2), before day 3 topotecan (D3-post 1), and 5 minutes after day 3 topotecan (D3-post 2). (B) γH2AX in plucked hairs with all data plotted as γH2AX signal intensities. γH2AX induction in patients who received topotecan only (patients 1 to 6) shows DNA double-stranded breaks after topotecan alone (left; n = 6). Patients who received M6620 plus topotecan on day 2 (patients 7 to 21) had increased DNA damage levels on day 3 compared with day 2, which was not the case for those who received topotecan alone on day 2 (right; n = 12). To understand the kinetics of γH2AX formation further, we obtained hair follicles at additional time points: 30 minutes to 1 hour after day 2 M6620 infusion (D2-post 2) and before day 3 topotecan (D3-post 1). (C) γH2AX in plucked hairs with all data plotted as γH2AX signal intensities in six patients who had additional sampling. Although follicles obtained 30 to 60 minutes after M6620 infusion on day 2 showed a decrease in γH2AX signal, an increase in H2AX phosphorylation was observed in follicles obtained 24 hours after M6620 infusion (before any additional topotecan). (D) Representative images of γH2AX staining in plucked hair bulbs collected from patient 14 (green, γH2AX; red, DNA). Original magnification x63. (E) γH2AX in PBMCs, with all data plotted as γH2AX foci per cells in patients who received topotecan only (left; n = 6) and in patients who received both topotecan and M6620 (right; n = 15). (F) Representative images of γH2AX staining in PBMCs (green, γH2AX; red, DNA). Original magnification x63. P values for the paired differences appear on the plots. The γH2AX signal intensities are expressed in arbitrary unit.