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A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple
Beata Holkova1, Adriana Zingone2, Maciej Kmieciak3
1Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia. Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia. beata.holkova@vcuhealth.org stgrant@vcu.edu.
Purpose:
AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma cells. This phase II study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory multiple myeloma.
Experimental Design:
AZD6244 (75 mg) was administered orally, twice a day, continuously for 28-day cycles. Response was evaluated after three cycles.
Results:
Thirty-six patients received therapy. The median age was 65 years (range: 43-81) and the median number of prior therapies was 5 (range: 2-11). The most common grade 3 and 4 toxicities included anemia, neutropenia, thrombocytopenia, diarrhea, and fatigue. Three deaths occurred possibly related to AZD6244 (2 due to sepsis, 1 due to acute kidney injury). After AZD6244 discontinuation, three additional deaths occurred due to disease progression. The response rate (CR + PR) was 5.6% with a mean duration of response of 4.95 months and median progression-free survival time of 3.52 months. One patient had a very good partial response (VGPR), 1 patient had a partial response, 17 patients had stable disease, 13 patients had progressive disease, and 4 patients could not be assessed for response. Pharmacodynamic studies revealed variable effects on bone marrow CD138(+) cell MEK1/2 and ERK1/2 phosphorylation. The best clinical response, a prolonged VGPR, occurred in a patient with an MMSET translocation.
Conclusions:
Single-agent AZD6244 was tolerable and had minimal activity in this heavily pretreated population.
Insights
Single-agent AZD6244 showed minimal activity in relapsed/refractory multiple myeloma patients. The MEK1/2 inhibitor was tolerable but demonstrated a low response rate in this heavily pretreated population.
Area of Science:
- Oncology
- Pharmacology
Background:
- Multiple myeloma is a hematologic malignancy characterized by uncontrolled proliferation of plasma cells.
- Targeted therapies, including MEK inhibitors, are being investigated for their potential in treating relapsed or refractory multiple myeloma.
- AZD6244 is a potent and selective inhibitor of MEK1 and MEK2 kinases, enzymes crucial in the MAPK/ERK signaling pathway.
Purpose of the Study:
- To evaluate the response rate of AZD6244 in patients with relapsed or refractory multiple myeloma.
- To assess the safety and tolerability of AZD6244 in this patient population.
Main Methods:
- A phase II clinical trial employing a two-stage Simon design.
- AZD6244 was administered orally at 75 mg twice daily for 28-day cycles.
- Response was assessed after three cycles of treatment.
Main Results:
- Thirty-six heavily pretreated patients received AZD6244. The overall response rate (CR+PR) was 5.6%.
- Common toxicities included anemia, neutropenia, thrombocytopenia, diarrhea, and fatigue. Three treatment-related deaths occurred.
- Median progression-free survival was 3.52 months. One patient achieved a very good partial response (VGPR).
Conclusions:
- Single-agent AZD6244 demonstrated tolerable safety but minimal clinical activity in relapsed or refractory multiple myeloma.
- The MEK1/2 inhibitor showed limited efficacy in this heavily pretreated patient group.
- Further investigation of AZD6244, potentially in combination therapies, may be warranted.
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