An Open Label Phase I Dose Escalation Trial of Intravenous BI 6727 (Volasertib)in Combination With Oral BIBW 2992 (Afatinib) in Patients With Advanced Solid Tumours

Lead sponsor

Boehringer Ingelheim is the lead sponsor of 2,245 studies on the registry; 58 are open to participants now.

Of its 162 completed or terminated interventional studies of FDA-regulated products, 116 (72%) have results posted.

Study arms

• Experimental
  two experimental arms

  patients receive increasing doses of BI 6727 in combination with increasing doses of BIBW 2992

  Drug: BI 6727 + BIBW 2992

Interventions

• DrugBI 6727 + BIBW 2992

  BI 6727 administered i.v. every 21 days + BIBW 2992 given orally once a day

Primary outcomes

1. Number of Participants With Dose Limiting Toxicities (DLT)

   MTD was defined on the basis of DLTs occuring during Cycle 1 of the dose escalation part in each of the 2 treatment schedules. DLTs were defined as drug related based on Common Terminology Criteria for AE's (CTCAE) Grade(G) :1) G4 neutropenia (ANC, including bands, \<500/mm³) for more than 7 days, 2) G3 or 4 neutropenia associated with fever \>38.5° C (febrile neutropenia),3) Neutropenic infection G ≥3, 4) G4 thrombocytopenia or G3 thrombocytopenia associated with bleeding requiring whole blood transfusion.5) Non-haematological G ≥3 toxicity excluding: (a) untreated G3 diarrhoea, (b) untreated G3 nausea and/or vomiting, (c) untreated G3 rash. 6) G2 increase in AST and/or ALT in conjunction with an elevated bilirubin level of G ≥2, 7) G2 nausea and/or vomiting despite optimal supportive/antiemetic treatment for at least 7consecutive days. 8) G2 diarrhoea for 2 or more consecutive days despite antidiarrhoeal medication/hydration, 9) Decrease in left ventricular function G ≥2.

   Time frame: 22 Days

2. Maximum Tolerable Dose (MTD) of Two Combination Therapy of Volasertib and Afatinib.

   Maximum Tolerable Dose (MTD) was determined by dose escalation for volasertib and afatinib. The "3 + 3 design with de-escalation" for both the Schedules A and B. Patients were sequentially allocated to the dose cohorts. Apart from allocation to the treatment schedules, escalation and/or de-escalation to determine the MTD occurred independently within the 2 dose schedules. Cohorts of 3 patients were to be treated at the starting dose levels according to the treatment schedule. Before entering patients at a higher dose level, all patients at the previous dose level combination had to complete at least the initial cycle of 21 days.

   Time frame: MTD was assessed during the first cycle of combination of Volasertib and Afatinib therapy (22 days)

Secondary outcomes

1. Number of Patients With Drug-related Adverse Events According to Common Terminology Criteria for Adverse Events (CTCAE) Criteria v 3.0

   Number of patients with investigator defined drug-related adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) criteria v 3.0

   Time frame: After the first drug administration until 28 days after the last drug administration, up to 413 days.

2. Number of Patients With Objective Response (OR)

   Objective tumor response based on response evaluation criteria in solid tumors (RECIST) version 1.1. OR is defined as complete response (CR) or partial response (PR). As Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by using appropriate radiology techniques: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions.

   Time frame: Tumor assessment was performed at screening and at the end of every 3 treatment cycle (ie every 9 weeks of treatment).

3. Number of Patients With Best Overall Response.

   Best overall response based on response evaluation criteria in solid tumors (RECIST) version 1.1. Best overall response is defined as complete response, partial response, stable disease, progressive disease or not evaluable. As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by using appropriate radiology techniques: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.

   Time frame: Tumor assessment was performed at screening and at the end of every 3 treatment cycle (ie every 9 weeks of treatment).

4. Number of Patients With Disease Control

   Disease control based on response evaluation criteria in solid tumors (RECIST) version 1.1. Patients who had a best overall tumour response of complete response (CR), partial response (PR) or stable disease (SD) were assessed to show disease control. As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by using appropriate radiology techniques: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.

   Time frame: Tumor assessment was performed at screening and at the end of every 3 treatment cycle (ie every 9 weeks of treatment).

Baseline characteristics

Publications

• Machiels JP, Peeters M, Herremans C, Surmont V, Specenier P, De Smet M, Pilz K, Strelkowa N, Liu D, Rottey S. A phase I study of volasertib combined with afatinib, in advanced solid tumors. Cancer Chemother Pharmacol. 2015 Oct;76(4):843-51. doi: 10.1007/s00280-015-2860-2. Epub 2015 Sep 8. PubMed 26349473 ↗