Lartruvo - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One mL of concentrate for solution for infusion contains 10 mg of olaratumab.

-0

Each 19 mL vial contains 190 mg of olaratumab.

Each 50 mL vial contains 500 mg of olaratumab.

Olaratumab is a human IgG1 monoclonal antibody produced in murine (NS0) cells by recombinant DNA technology.

Excipient with known effect

Each 19mL vial contains approximately 22 mg (1 mmol) sodium.

Each 50 mL vial contains approximately 57 mg (2.5 mmol) sodium.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate).

The concentrate is clear to slightly opalescent and colourless to slightly yellow solution without visible particles.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Lartruvo is indicated in combination with doxorubicin for the treatment of adult patients with advanced soft tissue sarcoma who are not amenable to curative treatment with surgery or radiotherapy and who have not been previously treated with doxorubicin (see section 5.1).

4.2 Posology and method of administration

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Infusion-related reactions (IRRs), including anaphylactic reactions, were reported in clinical trials with olaratumab. The majority of these reactions occurred during or following the first olaratumab infusion. Symptoms of IRRs included flushing, shortness of breath, bronchospasm, or fever/chills, and in some cases manifested as severe hypotension, anaphylactic shock, or fatal cardiac arrest. Severe IRRs such as anaphylactic reactions can occur despite the use of premedication. Patients should be monitored during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. For management and dose adjustments in patients who experience Grade 1 or 2 IRR during the infusion, see section 4.2. In patients who have experienced a previous Grade 1 or 2 IRR, premedication with diphenhydramine hydrochloride (intravenously), paracetamol, and dexamethasone is recommended. Olaratumab should be immediately and permanently discontinued in patients who experience Grade 3 or 4 IRR (see sections 4.2 and 4.8).

Neutropenia

Patients receiving olaratumab and doxorubicin are at risk of neutropenia (see section 4.8). Neutrophil count should be checked prior to Olaratumab dosing on Day 1 and Day 8 of each cycle. Neutrophil count should be monitored during the treatment with olaratumab and doxorubicin and supportive care should be administered such as antibiotics or G-CSF as per local guidelines. For dosage adjustments related to neutropenia, refer to section 4.2.

Haemorrhagic events

Patients receiving olaratumab and doxorubicin are at risk of haemorrhagic events (see section 4.8). Platelet counts should be checked prior to olaratumab dosing on Day 1 and Day 8 of each cycle. Coagulation parameters should be monitored in patients with conditions predisposing to bleeding, such as anticoagulant use. In a study of olaratumab in combination with liposomal doxorubicin, was one case of fatal intracranial haemorrhage in a patient who had experienced a fall while on treatment.

Anthracycline pre-treated patients

The risk of cardiac toxicity rises with increasing cumulative doses of anthracyclines, including doxorubicin. There are no data for the combination of olaratumab and doxorubicin in anthracycline pre-treated patients, including pre-treatment with doxorubicin (see section 4.1).

Sodium restricted diet

This medicinal product contains 22 mg sodium per each 19 m 50 mL vial. To be taken into consideration by patients on a co

Cardiac toxicity

Doxorubicin can cause cardiotoxicity. The risk of toxicity rises with increasing cumulative doses and is higher in individuals with a history of cardiomyopathy, mediastinal irradiation or pre-existing cardiac disease. To minimise doxorubicin-related cardiotoxicity, the use of appropriate cardio-

protective measures (LVEF measurement, such

use of cardioprotective agents) should be considered and planned in all patients before the start and throughout the treatment.

Please refer to

In the phase 2 trial, patients in both treatment groups that received 5 or more cycles of doxorubicin received dexrazoxane prior to each dose of doxorubicin from cycle 5 onwards to minimize the risk of doxorubicin-related cardiotoxicity (see sections 4.8 and 5.1).

idly metabolised and predominantly eliminated by the biliary system, the toxicity anced in patients with hepatic impairment. Refer to doxorubicin SmPC for

itoring of hepatic function and doxorubicin dose adjustments in patients with impaired

4.5 Interaction with other medicinal products and other forms of interaction

Olaratumab is a human monoclonal antibody. In a dedicated DDI study, no pharmacokinetic interactions were observed in patients between olaratumab and doxorubicin.

No other formal DDI studies with olaratumab and medicinal products commonly used in cancer patients, including those with STS (e.g. antiemetics, analgesics, anti-diarrheal drugs, oral contraceptives, etc.), have been performed.

As monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymes or other drug metabolising enzymes, inhibition or induction of these enzymes by co-administered medicinal products is not anticipated to affect the pharmacokinetics of olaratumab. Conversely, olaratumab is not anticipated to affect the pharmacokinetics of co-administered medicinal products.

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including doxorubicin may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving olaratumab in combination with doxorubicin.

4.6 Fertility, pregnancy and lactation

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.

Pregnancy

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 PDGFRa antibody in mice showed foetal malformations and skeletal alterations (see section 5.3).

Based on its mechanism of action (see section 5.1), 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.

Breast-feeding

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.

Fertility

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

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

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 (see section 4.4) 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. For dose adjustments, refer to section 4.2

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 1/2 and were confounded by multiple factors. Three Grade >3 events, including one fatal, have been reported across the clinicalN development programme of olaratumab (see section 4.4).

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 (see section 4.2). The rates of discontinuation were comparable between treatment arms across all age groups.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

There is no experience with Lartruvo overdose in human clinical trials. Lartruvo has been administered in a Phase 1 study up to 20 mg/kg on days 1 and 8 of a 21 day cycle without reaching a maximum tolerated dose. In case of overdose, use supportive therapy. There is no known antidote to Lartruvo overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC27

Mechanism of action

Olaratumab is an antagonist of platelet derived growth factor receptor-a (PDGFR-a), expressed on tumour and stromal cells. Olaratumab is a targeted, recombinant, fully human immunoglobulin G subclass 1 (IgG1) monoclonal antibody that specifically binds PDGFR-a, blocking PDGF AA, -BB, and -CC binding and receptor activation. As a result, in vitro olaratumab inhibits PDGFR-a pathway signalling in tumour and stromal cells. In addition, in vivo olaratumab has been shown to disrupt the PDGFR-a pathway in tumour cells and inhibit tumour growth.

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity.

Overall, a low incidence of both treatment emergent anti-drug antibodies and neutralising antibodies were detected in clinical trial samples.

Clinical efficacy and safety

The efficacy and safety of olaratumab was assessed in a Phase 1b/2, multi-centre study in anthracycline naïve patients with histologically or cytologically confirmed, advanced soft tissue sarcoma not amenable to receive surgery or radiotherapy with curative intent. Patients with gastrointestinal stromal tumours (GIST) or Kaposi sarcoma were not enrolled. The Phase 2 portion of

the study was a randomised, open label study of olaratumab plus doxorubicin versus doxorubicin alone. A total of 133 patients were randomised, of whom 129 received at least one dose of study treatment (64 in the olaratumab plus doxorubicin arm and 65 in the doxorubicin arm). Patients required to have histologically or cytologically confirmed, advanced soft tissue sarcoma and E performance status of 0–2. Randomisation was stratified by PDGFR-a expression (positive v negative), number of previous lines of treatment (0 versus 1 or more lines), histological tu (leiomyosarcoma, synovial sarcoma, and others) and ECOG performance status (0 or

Patients were randomised in a 1:1 ratio to either olaratumab (15 mg/kg) on Day 1 and Day 8 plus doxorubicin (75 mg/m2) on Day 1 of each 21-day cycle for up to 8 cycles or doxorubicin (75 mg/m2) alone on Day 1 of each 21-day cycle, also for up to 8 cycles. Olaratumab and doxorubicin were administered by intravenous infusion. During Cycles 5 to 8 on both arms, dexrazoxane (dosed at a ratio of 10:1 to the administered dose of doxorubicin) could be administered on Day 1 of each cycle at the investigator’s dis­cretion to reduce potential doxorubicin-related cardiotoxicity. All patients receiving more than 4 cycles of doxorubicin received dexrazoxane. Patients in the olaratumab plus doxorubicin arm could continue on olaratumab monotherapy until disease progression, unacceptable

toxicity or any other reason for treatment discontinuation population. The main analysis was performed in the following two subgroups: Leiomyosarcoma (LMS) and non-LMS (other). Subgroups analysis of OS is shown in figure 2. Difference in objective response rate [complete response (CR) + partial response (PR)] according to investigator assessment was not statistically significant (18.2 % vs 11.9 % in patients randomised to olaratumab plus doxorubicin compared to patients randomized to doxorubicin respectively).

Efficacy results are shown in Table 3 and Figures 1 and 2.

Table 3. Summary of survival data – ITT population

Abbreviations: CI = confidence interval

* By investigator assessment

Met phase 2 protocol defined significance level of 0.19

tn

2 0) > O

_ Investigalional Arm Control Arm

Number at Risk

Investigational Arm 61

Control Arm

is administered as an intravenous infusion only.

Distribution

The population pharmacokinetic (PopPK) model-based mean (CV %) volume of distribution of olaratumab at steady state (Vss) was 7.7 L (16 %).

Elimination

The PopPK model-based mean (CV %) clearance for olaratumab was 0.56 L/day (33 %). This corresponds to a mean terminal half-life of approximately 11 days.

Special populations

Age, sex, and race had no clinically meaningful effect on the PK of olaratumab based on a PopPK analysis. Clearance and volume of distribution had a positive correlation with body weight.

Renal impairment

No formal studies have been conducted to evaluate the effect of renal impairment on the PK of olaratumab. Based on a PopPK analysis, no clinically meaningful differences in the clearance of olaratumab were observed in patients with mild (calculated creatinine clearance [CLcr] 60–89 mL/min, n = 43), or moderate (CLcr 30–59 mL/min, n = 15) renal impairment compared to patients with normal renal function (CLcr >90 mL/min, n = 85). No data were available from patients with severe renal impairment (CLcr 15–29 mL/min).

Hepatic impairment

No formal studies have been conducted to evaluate the effect of hepatic impairment on the PK of olaratumab. Based on a PopPK analysis, no clinically meaningful differences in the clearance of olaratumab were observed in patients with mild (total bilirubin within upper limit of normal [ULN] and AST>ULN, or total bilirubin > 1.0–1.5 times ULN and any AST level, n = 16), or moderate (tota bilirubin > 1.5–3.0 times ULN, n = 1) hepatic impairment compared to patients with normal hepatic function (total bilirubin and AST < ULN, n = 126). No data were available from          th severe

hepatic impairment (total bilirubin > 3.0 times ULN and any AST level).

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on repeat do monkeys.

No animal studies have been performed to test olaratumab for potential of carcinogenicity, genotoxicity, or fertility impairment. Administration of an anti-murine PDGFR- a surrogate antibody to pregnant mice during organogenesis at 50 and 150 mg/ sulted in increased malformations (abnormal eyelid development) and skeletal alterations (f     l/parietal additional ossification site).

The foetal effects in mice administered the surrogate anti     occurred at exposures less than the

AUC exposure at the maximum recommended human dose of 15 mg/kg olaratumab.

6.1 List of excipients

Mannitol (E421)

Glycine (E640) Sodium chloride L-Histidine monohydrochloride monohydrate L-Histidine Polysorbate 20 Water for injec

6.2

The medicinal product should not be administered or mixed with dextrose containing solutions.

6.3 Shelf life

Unopened vial

2 years.

After dilution

This product is preservative free. From a microbiological point of view the prepared dosing solution should be used immediately. If not used immediately, the dosing solution should be stored under refrigeration for up to 24 hours at 2 °C to 8 °C and up to an additional 8 hours at room temperature (up to 25 °C) assuming dilution has taken place in controlled and validated aseptic conditions. Storage times include the duration of infusion.

6.4 Special precautions for storage

Store in a refrigerator (2° C – 8° C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

a polypropylene cap.

50 mL solution in a vial (Type I glass) with a chlorobutyl elastomeric stopper, a polypropylene cap.

Pack of 1 vial of 19 mL.

Pack of 2 vials of 19 mL.

Pack of 1 vial of 50 mL.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handlingto ensure the sterility of the prepared

The infusion solution should be prepared using aseptic solution.

Each vial is intended for single use only. Do inspected for particulate matter and discolou clear to slightly opalescent and colourles administration. If particulate matter dose and volume of olaratumab nee contain 190 mg or 500 mg as 9 mg/mL (0.9 %) solution fo

In case of prefilled intraven us infusion container usage

Based on the calculated volume of olaratumab, the corresponding volume of sodium chloride

9 mg/mL (0.9 %) solution for injection should be removed from the prefilled 250 mL intravenous container. The calculated volume of olaratumab should be aseptically transferred to the intravenous container. The final total volume in the container should be 250 mL. The container should be gently inverted to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution.

In case of empty intravenous infusion container usage

The calculated volume of olaratumab should be aseptically transferred into an empty intravenous infusion container. A sufficient quantity of sodium chloride 9 mg/mL (0.9 %) solution for injection should be added to the container to make the total volume 250 mL. The container should be gently inverted to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution.

Administer via an infusion pump. A separate infusion line must be used and the line must be flushed with sodium chloride 9 mg/mL (0.9 %) solution for injection at the end of the infusion.

Any unused portion of olaratumab left in a vial should be discarded, as the product contains no antimicrobial preservatives.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Eli Lilly Nederland B.V. Papendorpseweg 83 3528 BJ Utrecht

The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUT

Date of first authorisation: 9 November 2016

Date of latest renewal: 21 September 2017