Phase I dose-escalation study of milciclib in combination with gemcitabine in patients with refractory solid tumors

Our plain-English summary of Phase I dose-escalation study of milciclib in combination with gemcitabine in patients with refractory solid tumors, by S. Aspeslagh, K. Shailubhai, R. Bahleda, et al (Cancer Chemotherapy and Pharmacology, 2017).

The study

• Authors: S. Aspeslagh, K. Shailubhai, R. Bahleda, A. Gazzah, A. Varga, A. Hollebecque, C. Massard, A. Spreafico, M. Reni, J.C. Soria
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2017;79(6):1257-1265
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: This phase I trial evaluated the safety and tolerability of milciclib, an inhibitor of multiple cyclin-dependent kinases and tropomycin receptor kinase A, in combination with gemcitabine in patients with refractory solid tumors.

Design: Sixteen patients were enrolled and treated with milciclib at three dose levels (45 mg/m2/day, n = 3; 60 mg/m2/day, n = 3; and 80 mg/m2/day, n = 10) with a fixed dose of gemcitabine (1000 mg/m2/day). Milciclib was administered orally once daily for 7 days on/7 days off in a 4-week cycle, and gemcitabine was administered intravenously on days 1, 8 and 15 in a 4-week cycle.

Results: All 16 enrolled patients were evaluable for safety and toxicity. Dose-limiting toxicities, which occurred in only one out of nine patients treated at the maximum dose tested (milciclib 80 mg/m2/day and gemcitabine 1000 mg/m2/day), consisted of Grade 4 thrombocytopenia, Grade 3 ataxia and Grade 2 tremors in the same patient. Most frequent treatment-related AEs were neutropenia and thrombocytopenia. Among 14 evaluable patients, one NSCLC patient showed partial response and 4 patients (one each with thyroid, prostatic, pancreatic carcinoma and peritoneal mesothelioma) showed long-term disease stabilization (>6-14 months). Pharmacokinetics of the orally administered milciclib (~t1/2 33 h) was not altered by concomitant treatment with gemcitabine.

Conclusion: The combination treatment was well tolerated with manageable toxicities. The recommended phase II dose was 80 mg/m2/day for milciclib and 1000 mg/m2/day for gemcitabine. This combination treatment regimen showed encouraging clinical benefit in ~36% patients, including gemcitabine refractory patients. These results support further development of combination therapies with milciclib in advanced cancer patients.

In plain English

This was a small early-stage (phase I) drug trial, not a study of asbestos exposure. At one French and one Italian centre, 16 adults (median age 61.0 years) took the experimental pill milciclib at one of three doses (45, 60 or 80 mg/m2/day) plus a fixed dose of the chemotherapy drug gemcitabine. Their advanced solid tumours had stopped responding to standard treatment or had no standard treatment. Three had mesothelioma. Severe (Grade 3 to 4) drug-related side effects occurred in 10 patients (62.5%), most often low white blood cell or platelet counts. No deaths occurred during treatment. Two patients developed thrombotic microangiopathy, a disorder of small blood vessels, after 14 and 21 months, and both recovered. Of 14 patients whose tumours could be assessed, one with lung cancer had a partial response. Four had disease that stayed stable for 6 months or more, including one patient with peritoneal mesothelioma (13.4 months). The authors recommended the 80 mg/m2/day dose and concluded the combination showed acceptable toxicity and some encouraging response. They noted the small numbers limited firm conclusions.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase I, multicentre, open-label, dose-escalation drug trial
• Who was studied: 16 patients (13 men, 3 women; median age 61.0 years) with advanced solid tumours, treated at two centres (one in France, one in Italy). To be eligible, patients had to be refractory to standard therapy or have no standard therapy available. Cancer types were lung (31.3%), mesothelioma (18.8%, 3 patients), pancreatic, colorectal and prostate (12.5% each), and thymoma and thyroid (6.3% each). No study dates are given.
• Exposure: No asbestos exposure was studied. The intervention was oral milciclib at 45, 60 or 80 mg/m2/day (7 days on, 7 days off, in 4-week cycles) combined with intravenous gemcitabine at a fixed 1000 mg/m2/day on days 1, 8 and 15 of each 4-week cycle.
• Main results:
  • One first-cycle dose-limiting toxicity (Grade 4 thrombocytopenia, a low platelet count) occurred in 1 of 9 evaluable patients at the 80/1000 mg/m2 dose. On that basis, 80 mg/m2/day milciclib was set as the recommended phase II dose.
  • Drug-related Grade 3 to 4 adverse events occurred in 10 of 16 patients (62.5%), 7 of them at the highest dose level. No deaths occurred during study treatment.
  • Neutropenia (low white blood cell count) and thrombocytopenia were drug-related in 68.8% of patients. Grade 3 to 4 neutropenia occurred in 43.8% and Grade 3 to 4 thrombocytopenia in 25.0%.
  • Two patients developed thrombotic microangiopathy after 14 and 21 months of treatment, and both recovered.
  • Among 14 evaluable patients, 1 (7.1%), a patient with non-small-cell lung cancer, had a partial response, and 10 (71.4%) had stable disease.
  • Disease stabilisation lasting 6 months or more occurred in 4 of 14 evaluable patients (28.6%), with thyroid, prostatic or pancreatic carcinoma or peritoneal mesothelioma. It lasted 13.4 months in the peritoneal mesothelioma patient and 14.3 months in the prostate cancer patient.
  • The pharmacokinetic measures of milciclib and gemcitabine given together were consistent with earlier single-drug data. Milciclib plasma levels decayed with a half-life of about 40 h.
• The authors' conclusion: The authors concluded that the milciclib and gemcitabine combination showed acceptable toxicity and some encouraging clinical response, and should be further explored for other solid cancers.
• Limitations the authors state:
  • Because the sample was small and the patients were heavily pretreated, the authors could not reach a definite conclusion on milciclib's role in the severe blood-count side effects.
  • The numbers of patients previously treated with gemcitabine were too small to draw conclusions about whether the combination overcame gemcitabine resistance.
  • The patients were heavily pretreated and were not selected for molecular alterations.
  • The two cases of thrombotic microangiopathy were interpreted against a very small denominator of 16 patients.

Topics

Medical terms in this study, explained in our Lexicon: Gemcitabine, Neutropenia, Carcinoma, Peritoneal Mesothelioma.

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