Olaratumab

If neutropenic fever/infection or Grade 4 neutropenia lasting longer than 1 week occurs, administration of olaratumab should be temporarily discontinued until the absolute neutrophil count is 1,000/µL or higher and then the dose of olaratumab should be resumed at the reduced dose of 12 mg/kg. If neutropenic fever/infection or Grade 4 neutropenia lasting longer than 1 week recurs despite dose reduction, the dose should be reduced further to 10 mg/kg.

There are no or limited amount of data from the use of olaratumab in pregnant women. Reproductive and development toxicity study conducted with an anti-murine PDGFRα antibody in mice showed foetal malformations and skeletal alterations. Based on its mechanism of action, olaratumab has the potential to cause foetal harm. Olaratumab is not recommended during pregnancy and in women of childbearing potential not using contraception, unless the potential benefit justifies the potential risk to the foetus.

It is not known whether olaratumab is excreted in human milk. Human IgG is excreted in human milk, therefore breast-feeding is not recommended during treatment with olaratumab and for at least 3 months following the last dose.

Women of childbearing potential/contraception in females

Women of childbearing potential should be advised to avoid becoming pregnant while on olaratumab and should be informed of the potential hazard to the pregnancy and foetus. Women of childbearing potential should be advised to use effective contraception during treatment and for at least 3 months following the last dose of olaratumab.

Fertility

There are no data on the effect of olaratumab on human fertility.

Olaratumab may have minor influence on the ability to drive and use machines. Due to frequent occurrence of fatigue, patients should be advised to use caution when driving or operating machinery.

Summary of the safety profile

Olaratumab-treated patients from Phase 2 study

In the olaratumab plus doxorubicin arm, the most serious (Grade ≥3) adverse drug reactions (ADRs) observed were neutropenia (54.7%) and musculoskeletal pain (7.8%). The most frequently occurring ADRs were nausea, musculoskeletal pain, neutropenia and mucositis.

The most frequent ADRs associated with permanent treatment discontinuation occurred in 3 (4.7%) patients of which the most frequent were infusion-related reactions (3.1%) and mucositis (1.6%).

Known toxicities reported for doxorubicin, observed in the combination of olaratumab and doxorubicin include fatigue, anaemia, thrombocytopenia and alopecia. Please refer to the doxorubicin SmPC for complete descriptions of all adverse events associated with doxorubicin treatment

Tabulated list of adverse reactions

ADRs which were reported in patients with soft tissue sarcoma treated with olaratumab in combination with doxorubicin in the Phase 2 study are listed below in table in MedDRA body system organ class, frequency and grade of severity. The following convention has been used for classification of frequency: Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000).

Within each frequency grouping, ADRs are presented in order of decreasing seriousness.

Adverse reactions in patients receiving olaratumab plus doxorubicin for soft tissue sarcoma during the Phase 2 portion of a Phase 1b/2 study:

^a Refer to NCI CTCAE Criteria (Version 4.03) for each Grade of toxicity
^b Musculoskeletal pain includes arthralgia, back pain, bone pain, flank pain, groin pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, muscle spasms, neck pain, and pain in extremity.
^c Infusion-related reactions includes anaphylactic reactions/anaphylactic shock.

Description of selected ADRs

Infusion-related reactions (IRRs)

IRRs were reported in 12.5% of patients and mainly present as chills, fever or dyspnoea. Severe IRRs, also including a fatal case were reported in 3.1% of patients and mainly presented with shortness of breath, loss of consciousness and hypotension. All severe IRRs occurred during or immediately after the first administration of olaratumab.

Neutropenia

In the phase 2 trial, the incidence of neutropenia was 59.4% (all Grades) and 54.7% (Grade 3) in the olaratumab plus doxorubicin arm and 38.5% (all Grades) and 33.8% (Grade 3) in the doxorubicin alone arm. The rate of febrile neutropenia was 12.5% in the olaratumab plus doxorubicin arm and 13.8% in the doxorubicin alone arm.

Musculoskeletal pain

In the phase 2 trial the incidence of Musculoskeletal pain was 64.1% (all Grades) and 7.8% (Grade 3) in the olaratumab plus doxorubicin arm and 24.6% (all Grades) and 1.5% (Grade 3) in the doxorubicin alone arm. In the majority of patients the pain was related to the patients' underlying cancer or metastases or pre-existing or concomitant conditions. The majority of these events occurred in the first 4 cycles. The pain can last from few days to up to 200 days. In some patients there was a recurrence of pain .The pain did not worsen with time or during recurrence.

Cardiac toxicity

No clinically meaningful difference in doxorubicin-related cardiotoxicity was observed between the two treatment arms of the study. The rate of cardiac arrhythmias was similar in both arms (15.6% in the Investigational Arm and 15.4% in the Control Arm). The rate of treatment-emergent cardiac dysfunction was comparable between the two treatment arms (7.8% in the Investigational Arm and 6.2% in the Control Arm).

Haemorrhagic events

In the phase 2 trial, the frequency of haemorrhagic events considered related to any study drug was 3.1% in either treatment arm. All of these events were Grade ½ and were confounded by multiple factors. Three Grade ≥3 events, including one fatal, have been reported across the clinical development programme of olaratumab.

Toxicity in the elderly

There was a higher incidence of Grade ≥3 adverse reactions, adverse reactions leading to discontinuation and a higher rate of haematological toxicity in the elderly population compared to the overall study population. The rates of discontinuation were comparable between treatment arms across all age groups.