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Olaratumab

Pronunciation

(oh lar AT ue mab)

Index Terms

  • Anti-PDGFR Alpha Monoclonal Antibody IMC-3G3
  • IMC-3G3
  • LY3012207

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Lartruvo: 500 mg/50 mL (50 mL)

Brand Names: U.S.

  • Lartruvo

Pharmacologic Category

  • Antineoplastic Agent, Monoclonal Antibody
  • Antineoplastic Agent, PDGFR-alpha Blocker

Pharmacology

Olaratumab is a human (recombinant) IgG1 antibody which expressly binds to platelet-derived growth receptor alpha (PDGFR-α) to prevent binding of PDGF-AA, PDGF-BB, and PDGF-CC and block receptor activation and disrupt PDGF receptor signaling. The PDGF-alpha receptor has a role in cell differentiation, growth, and angiogenesis and has demonstrated antitumor activity in sarcomas (Tap 2016).

Distribution

Vss: 7.7 L

Half-Life Elimination

~11 days (range: 6 to 24 days)

Use: Labeled Indications

Soft tissue sarcoma: Treatment (in combination with doxorubicin) of adults with soft tissue sarcoma (STS) with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery.

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Dosing: Adult

Soft tissue sarcoma: IV: 15 mg/kg on days 1 and 8 every 3 weeks (in combination with doxorubicin) for 8 cycles; after 8 cycles are completed, continue olaratumab (as a single agent) until disease progression or unacceptable toxicity (Tap 2016).

Premedications: On day 1 of cycle 1, premedicate with diphenhydramine (25 to 50 mg IV) and dexamethasone (10 to 20 mg IV) prior to olaratumab.

Note: Dexrazoxane was allowed on day 1 of cycles 5 to 8 to reduce the potential for doxorubicin-related cardiotoxicity (Tap 2016).

Dosing: Renal Impairment

CrCl 30 to 89 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; however, mild to moderate impairment has no clinically relevant impact on olaratumab pharmacokinetics.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Mild (total bilirubin within normal limits and AST greater than the upper limit of normal [ULN] or total bilirubin >1 up to 1.5 times ULN and any AST) to moderate (total bilirubin >1.5 up to 3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer’s labeling; however, mild to moderate impairment has no clinically relevant impact on olaratumab pharmacokinetics.

Severe impairment (total bilirubin >3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Adjustment for Toxicity

Hematologic toxicity: Neutropenic fever/infection or grade 4 neutropenia lasting longer than 1 week: Withhold olaratumab until the absolute neutrophil count (ANC) is ≥1,000/mm3 and then resume with the dose permanently reduced to 12 mg/kg.

Infusion reaction:

Grade 1 or 2: Interrupt infusion; after resolution resume with the rate reduced by 50%.

Grade 3 or 4: Discontinue permanently.

Note: Doxorubicin may also require dosage modification.

Reconstitution

Withdraw calculated dose volume and dilute in NS to a total volume of 250 mL. Gently invert to mix (do not shake). Do not freeze the diluted solution. Dilute with NS only; do not use dextrose-containing or other solutions.

Administration

Infuse over 60 minutes. Do not infuse as an IV push or bolus. Flush the IV line with normal saline at the end of infusion.

If refrigerated, allow infusion solution to reach room temperature prior to administration. Infusion must be completed within 28 hours of dilution (when stored appropriately; see Storage/Stability).

Compatibility

Stable in NS. Incompatible in dextrose-containing solutions.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Keep in original carton to protect from light. Do not shake. Solutions diluted for infusion may be stored for up to 24 hours refrigerated and for an additional 4 hours at room temperature (infusion must be completed within this time frame). If refrigerated, allow infusion solution to reach room temperature prior to administration.

Drug Interactions

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Adverse Reactions

>10%:

Central nervous system: Fatigue (69%), neuropathy (22%), headache (20%), anxiety (11%)

Dermatologic: Alopecia (52%)

Endocrine & metabolic: Hyperglycemia (52%), hypokalemia (21%), hypophosphatemia (21%), hypomagnesemia (16%)

Gastrointestinal: Nausea (73%), mucositis (53%), vomiting (45%), diarrhea (34%), decreased appetite (31%), abdominal pain (23%)

Hematologic & oncologic: Lymphocytopenia (77%, grades 3/4: 44%), neutropenia (65%, grades 3/4: 48%), thrombocytopenia (63%, grades 3/4: 6%), prolonged partial thromboplastin time (33%, grades 3/4: 5%)

Hepatic: Increased serum alkaline phosphatase (16%)

Neuromuscular & skeletal: Musculoskeletal pain (64%)

Ophthalmic: Xerophthalmia (11%)

Miscellaneous: Infusion related reaction (13% to 14%)

1% to 10%: Immunologic: Development of IgG antibodies (4%; all patients had neutralizing antibodies; however, therapeutic effects of antibodies could not be assessed)

Warnings/Precautions

Concerns related to adverse effects:

• GI toxicity: Nausea, vomiting, diarrhea, mucositis, and abdominal pain have been reported, with a higher incidence in patients treated with olaratumab and doxorubicin, compared to doxorubicin alone.

• Hematologic toxicity: A higher incidence of grade 3 and 4 lymphopenia and neutropenia have been reported in patients treated with olaratumab and doxorubicin, compared to doxorubicin alone. Thrombocytopenia (all grades) also had a higher incidence in the combination arm.

• Infusion reaction: Olaratumab is associated with infusion reactions; most infusion reactions occurred with the first or second cycle. Grade 3 or higher reactions have occurred, including a fatal case. Symptoms of infusion reactions have included flushing, dyspnea, bronchospasm, and/or fever/chills; severe cases included hypotension, anaphylactic shock, or cardiac arrest. Premedication with diphenhydramine and dexamethasone is recommended. Monitor for signs/symptoms of infusion reactions during and after infusion (resuscitation equipment should be readily available). May require treatment interruption (followed by rate reduction) or permanent discontinuation.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

CBC with differential. Monitor for signs/symptoms of infusion reactions.

Pregnancy Considerations

Based on its mechanism of action, olaratumab would be expected to cause fetal harm if administered to a pregnant woman. Animal reproduction studies have not been conducted. Adequate contraception during therapy and for 3 months following the last dose is recommended in women of reproductive potential.

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