Phase Ib/II studies

On the basis of the favorable safety profile from the Phase I studies and preclinical data regarding olaratumab combination with doxorubicin in human sarcoma xenograft models,39,45 Tap et al26performed a multicentric, open-label Phase Ib and randomized Phase II study of doxorubicin alone or doxorubicin plus olaratumab in patients with unresectable or metastatic STSs, previously untreated with an anthracycline.


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The enrollment of Phase Ib–Phase II ran from October 2010 to January 2013.

The primary end point of Phase Ib was safety and that of Phase II was PFS, while OS, RR, safety, and pharmacokinetics were secondary end points.

In the Phase Ib part of the study, patients received olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m2) on day 1 of each 21-day cycle up to eight cycles. After eight cycles of the combination therapy, if no disease progression or unacceptable toxicities occurred, patients were allowed to receive olaratumab monotherapy until disease progression.

In the Phase II part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) plus doxorubicin (as described in the Phase Ib part) or doxorubicin alone (75 mg/m2) on day 1 of each 21-day cycle for up to eight cycles. After completion of eight cycles of doxorubicin, patients in the combination group could receive olaratumab monotherapy until disease progression, while patients in the doxorubicin-alone group were observed and could receive olaratumab monotherapy after disease progression.

Overall, 15 patients were enrolled and treated in the Phase Ib part of the study. In the Phase II portion, a total of 129 patients (out of 133 randomized patients) received at least one dose of the investigational therapy, including 64 patients who received the combination of olaratumab and doxorubicin (investigational arm) and 65 patients who received doxorubicin alone (control arm). A total of 30 patients treated in the control arm received olaratumab monotherapy after discontinuing doxorubicin, as permitted by the protocol. Baseline characteristics were well balanced in the two groups, except for a slight predominance of women in the investigational arm. Approximately 40% of patients were in the first-line setting; the remaining sample had performed at least one treatment line. The most represented histological subtypes were leiomyosarcoma (36% of patients in the investigational arm and 40% of patients in the control arm), undifferentiated pleomorphic sarcoma, and liposarcoma.

The Phase II primary end point was PFS. It was 6.6 months (95% CI 4.1–8.3 months) for patients treated with olaratumab plus doxorubicin and 4.1 months (95% CI 2.8–5.4 months) for those treated with doxorubicin monotherapy. This PFS improvement in favor of the experimental arm met the protocol-defined significance level of 0.1999 for final PFS (stratified HR 0.672, 95% CI 0.442–1.021,p=0.0615). Moreover, the most relevant finding of this study was the significant improvement in OS, which was a secondary end point, for patients treated in the experimental arm: final analysis of OS, performed after 91 (71%) patients had died in the intention-to-treat population, showed a median OS of 26.5 months (95% CI 20.9–31.7 months) with olaratumab plus doxorubicin vs 14.7 months (95% CI 9.2–17.1 months) with doxorubicin, with a gain of 11.8 months (HR 0.46, 95% CI 0.30–0.71,p=0.0003). This impressive benefit was consistent across the subgroup stratification factors, including histological tumor type (leiomyosarcoma vs non-leiomyosarcoma), number of previous treatments, and PDGFRα expression. PDGFRα expression, assessed by immunohistochemistry, did not show any predictive value on efficacy.

No difference in terms of objective RR was observed, which was 18.2% (9.8%–29.6%) for patients in the experimental arm compared with 11.9% (5.3–22.2) for patients in the control arm (p=0.3421).

AEs were more frequent with combination therapy vs doxorubicin alone and included neutropenia (58% vs 35%, respectively), mucositis (53% vs 35%, respectively), nausea (73% vs 52%, respectively), vomiting (45% vs 18%, respectively), and diarrhea (34% vs 23%, respectively). Grade 3 febrile neutropenia rate was similar in both groups (experimental arm 13% vs control arm 14%). The number of IRRs in the olaratumab plus doxorubicin arm was 13% vs 0% for doxorubicin. Cardiac toxicity is an expected risk of doxorubicin treatment, in particular with increasing cumulative exposure; however, the incidence of cardiac dysfunction in Phase II portion of the study was similar between the two treatment arms.

Ongoing trials

An ongoing double-blind, placebo-controlled, randomized Phase III study (ANNOUNCE trial, NCT02451943)49 was planned in order to confirm the survival advantage of olaratumab and to provide definitive drug confirmation by regulators. The primary end point of the study was OS, with an enrolled population of 460 patients. From August 2015 to June 2017, patients with unresectable or metastatic STSs were randomized to receive olaratumab plus doxorubicin vs placebo plus doxorubicin, with the same schedule used in the Phase II trial. The study is still ongoing, but the enrollment is closed. The first efficacy results are expected in 2019, and the study is expected to be completed in 2020. The Phase III ANNOUNCE study will enroll a higher number of patients compared with the Phase Ib/II trial, which will make the study more powerful and may help to detect tissue biomarkers to predict survival in treated patients. Preliminary data from post hoc biomarker analysis failed to identify a significant association between PDGFRα or PDGFRβ expression and OS or PFS in patients included in Tap et al’s Phase Ib/II study of doxorubicin with or without olaratumab. Low PDGF-BB or CXCR4 expression was associated with improved PFS in the combination arm.50

Recently, Barker et al51 presented results of a subgroup analysis including patients who received olaratumab monotherapy in the Phase II trial of Tap et al.26

The subgroup receiving olaratumab as maintenance of previous doxorubicin plus olaratumab treatment showed a median OS of 31.7 months and a 2-year survival rate of 67.6%. Conversely, the subgroup receiving olaratumab as a switch therapy after disease progression under doxorubicin showed a median OS of 13.5 months and a 2-year survival rate of 28.7%. These data, although not yet published, suggest a clinical benefit from olaratumab monotherapy as a maintenance strategy after a combination first-line treatment.

Several other trials are evaluating efficacy and safety of olaratumab in STS patients and are listed in Table 1.

(To view a larger version of Table 1, click here.)