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Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor.

Michael M, Vlahovic G, Khamly K, Pierce KJ, Guo F, Olszanski AJ - Br. J. Cancer (2010)

Bottom Line: The CP-868,596/docetaxel was escalated as above.The CP-868,596/docetaxel was well tolerated, but increased efficacy was not observed.Addition of axitinib delivered greater benefits than expected in the number of patients achieving prolonged stable disease with a moderate increase in AEs.

View Article: PubMed Central - PubMed

Affiliation: Peter MacCallum Cancer Centre, Consultant Medical Oncologist, Division of Haematology and Medical Oncology, Chair of GI Clinical Service, Locked Bag 1, A'Beckett Street, Victoria 8006, Australia. Michael.Michael@petermac.org

ABSTRACT

Background: Tumoural interstitial hypertension, possibly modulated by platelet-derived and vascular endothelial growth factor receptors (PDGFR and VEGFR), may mediate resistance to chemotherapy.

Methods: Forty-eight patients with advanced solid tumours received oral PDGFR inhibitor CP-868,596 (60-100 mg twice daily (BID)) and docetaxel (75-100 mg m⁻²), or CP-868,596 (60 mg BID), docetaxel (75 mg m⁻²), and VEGFR inhibitor axitinib (5 mg BID).

Results: The CP-868,596/docetaxel was escalated as above. The CP-868,596/docetaxel/axitinib was not dose escalated because of increased incidence of mucositis-like adverse events (AEs) with concurrent neutropenia relative to that expected for docetaxel. All tested regimens were tolerable, including 100 mg BID CP-868,596 (recommended phase II dose) plus 100 mg m⁻² docetaxel (maximum approved dose). Most treatment-emergent AEs were mild-moderate and reversible, commonly including nausea, diarrhoea, vomiting, constipation, fatigue, and anaemia (CP-868,596/docetaxel), and hypertension, lethargy, diarrhoea, and fatigue (CP-868,596/docetaxel/axitnib). Pharmacokinetics were unaffected by co-administration. Twenty-one patients achieved stable disease, including all seven evaluable on CP-868,596/docetaxel/axitinib. All nine CP-868,596/docetaxel/axitinib patients received therapy for a median of six (range, 3-16) cycles.

Conclusions: The CP-868,596/docetaxel was well tolerated, but increased efficacy was not observed. Addition of axitinib delivered greater benefits than expected in the number of patients achieving prolonged stable disease with a moderate increase in AEs.

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Related in: MedlinePlus

Dermatologic and metabolic responses in a 39-year-old male with metastatic epithelioid sarcoma. (A) Baseline PET scan. (B) Partial metabolic PET response following 14 days of CP-868,596 single-agent therapy. (C) Skin lesions prior to and (D) dermatologic response following 35 days of CP-868,596 single-agent therapy.
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fig1: Dermatologic and metabolic responses in a 39-year-old male with metastatic epithelioid sarcoma. (A) Baseline PET scan. (B) Partial metabolic PET response following 14 days of CP-868,596 single-agent therapy. (C) Skin lesions prior to and (D) dermatologic response following 35 days of CP-868,596 single-agent therapy.

Mentions: Within 4 weeks off trial, his skin lesions showed aggressive progression. Hence, he was retreated with CP-868,596 100 mg BID alone and within 2 weeks his pain again dramatically reduced. A fluordeoxyglucose positron emission tomography (FDG-PET) scan confirmed a partial metabolic response (Figure 1A and B). At 2 months, there was clinical improvement in his skin lesions (Figure 1C and D) and stable radiological disease. At 4 months, there was evidence of early progression and treatment was discontinued.


Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor.

Michael M, Vlahovic G, Khamly K, Pierce KJ, Guo F, Olszanski AJ - Br. J. Cancer (2010)

Dermatologic and metabolic responses in a 39-year-old male with metastatic epithelioid sarcoma. (A) Baseline PET scan. (B) Partial metabolic PET response following 14 days of CP-868,596 single-agent therapy. (C) Skin lesions prior to and (D) dermatologic response following 35 days of CP-868,596 single-agent therapy.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2990584&req=5

fig1: Dermatologic and metabolic responses in a 39-year-old male with metastatic epithelioid sarcoma. (A) Baseline PET scan. (B) Partial metabolic PET response following 14 days of CP-868,596 single-agent therapy. (C) Skin lesions prior to and (D) dermatologic response following 35 days of CP-868,596 single-agent therapy.
Mentions: Within 4 weeks off trial, his skin lesions showed aggressive progression. Hence, he was retreated with CP-868,596 100 mg BID alone and within 2 weeks his pain again dramatically reduced. A fluordeoxyglucose positron emission tomography (FDG-PET) scan confirmed a partial metabolic response (Figure 1A and B). At 2 months, there was clinical improvement in his skin lesions (Figure 1C and D) and stable radiological disease. At 4 months, there was evidence of early progression and treatment was discontinued.

Bottom Line: The CP-868,596/docetaxel was escalated as above.The CP-868,596/docetaxel was well tolerated, but increased efficacy was not observed.Addition of axitinib delivered greater benefits than expected in the number of patients achieving prolonged stable disease with a moderate increase in AEs.

View Article: PubMed Central - PubMed

Affiliation: Peter MacCallum Cancer Centre, Consultant Medical Oncologist, Division of Haematology and Medical Oncology, Chair of GI Clinical Service, Locked Bag 1, A'Beckett Street, Victoria 8006, Australia. Michael.Michael@petermac.org

ABSTRACT

Background: Tumoural interstitial hypertension, possibly modulated by platelet-derived and vascular endothelial growth factor receptors (PDGFR and VEGFR), may mediate resistance to chemotherapy.

Methods: Forty-eight patients with advanced solid tumours received oral PDGFR inhibitor CP-868,596 (60-100 mg twice daily (BID)) and docetaxel (75-100 mg m⁻²), or CP-868,596 (60 mg BID), docetaxel (75 mg m⁻²), and VEGFR inhibitor axitinib (5 mg BID).

Results: The CP-868,596/docetaxel was escalated as above. The CP-868,596/docetaxel/axitinib was not dose escalated because of increased incidence of mucositis-like adverse events (AEs) with concurrent neutropenia relative to that expected for docetaxel. All tested regimens were tolerable, including 100 mg BID CP-868,596 (recommended phase II dose) plus 100 mg m⁻² docetaxel (maximum approved dose). Most treatment-emergent AEs were mild-moderate and reversible, commonly including nausea, diarrhoea, vomiting, constipation, fatigue, and anaemia (CP-868,596/docetaxel), and hypertension, lethargy, diarrhoea, and fatigue (CP-868,596/docetaxel/axitnib). Pharmacokinetics were unaffected by co-administration. Twenty-one patients achieved stable disease, including all seven evaluable on CP-868,596/docetaxel/axitinib. All nine CP-868,596/docetaxel/axitinib patients received therapy for a median of six (range, 3-16) cycles.

Conclusions: The CP-868,596/docetaxel was well tolerated, but increased efficacy was not observed. Addition of axitinib delivered greater benefits than expected in the number of patients achieving prolonged stable disease with a moderate increase in AEs.

Show MeSH
Related in: MedlinePlus