Jeselhy

JESELHY tablets 40 mg: White to off-white, round, film-coated tablets debossed with "40" on one side, and "P116" on the other side.
Each JESELHY tablet contains 40 mg of pimitespib.
Excipients/Inactive Ingredients: Tablet core: Lactose hydrate, Corn starch, Hydroxypropylcellulose, Microcrystalline cellulose, Magnesium stearate.
Film coating: Hypromellose, Macrogol 6000, Titanium oxide, Magnesium stearate.

Pharmacotherapeutic group: Antineoplastic agents, heat shock protein 90 inhibitor.
Pharmacology: Pharmacodynamics: Mechanism of action: Pimitespib inhibits heat shock protein 90 (HSP90), a molecular chaperone that contributes to the stabilization of proteins, thereby leading to decrease the amounts of various client proteins, which are essential for the proliferation and survival of cancer cells.
Pimitespib inhibited the growth of the GIST-T1 human gastrointestinal stromal tumor-derived cell line (in vitro).
Pimitespib inhibited the tumor growth in the GIST-T1 human gastrointestinal stromal tumor xenograft mouse model (in vivo).
Pharmacodynamic effects: Two pharmacodynamics studies investigated the effects of pimitespib administration on biomarkers. In the first study, nude mice were administered pimitespib orally (5 mg/kg or 10 mg/kg) once, and heat shock protein 70 (HSP70) expression in peripheral blood mononuclear cells (PBMC) was measured. Dose-dependent induction of HSP70 was observed with this single administration of pimitespib. In the second study, nude mice bearing NCI-N87 tumor xenograft were administered pimitespib orally (5 mg/kg or 10 mg/kg once daily [QD]) for 14 days. Significant antitumor effect was observed in mice administered 5 mg/kg pimitespib, and a greater effect was observed in the 10 mg/kg group. Dose and time dependency of induction of HSP70 protein in PBMC as indicators for target engagement were also assessed. Both studies indicated that HSP70 protein expression in PBMC is a useful parameter for target engagement.
In clinical study 10058010, the induction of HSP70 after repeated administration of JESELHY occurred in a dose-dependent manner.
Clinical efficacy and safety: Phase 3 study (10058030 study): JESELHY at 160 mg or placebo was orally administered to 86 patients with unresectable or metastatic gastrointestinal stromal tumor that has progressed ^{Note 1)} after imatinib, sunitinib, and regorafenib once daily for 5 consecutive days, followed by 2 days off repeatedly. The treatment with JESELHY significantly prolonged progression-free survival based on modified RECIST ver. 1.1 ^{Note 2)} compared with placebo, of primary endpoint. (Data cut-off; 23 June 2020.)
Note 1) Patients with progression based on RECIST or clinical progression or intolerance to treatment with imatinib, sunitinib, and regorafenib were included.
Note 2) The following modified criteria were used from the standard RECIST ver. 1.1.
1. Selection of any lymph nodes as target lesions is not permitted.
2. Criteria for evaluation of new tumor nodule within pre-existing tumor mass.
(i) Tumor nodules within a pre-existing tumor mass that have a longest dimension of ≥2 cm and definitively active lesions enhanced with dynamic CT.
(ii) Lesions will be met on at least two sequential tumor assessments, which must be left at least ≥21 days between tumor assessments. (See Table 1 and figure.)

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Click on icon to see table/diagram/image

Adverse reactions occurred in 70 (93.3%) of 75 patients receiving JESELHY ^{Note 5)}. Major adverse reactions included diarrhoea (54 patients, 72%), decreased appetite (22 patients, 29.3%), blood creatinine increased (21 patients, 28%), malaise (20 patients, 26.7%), nausea (19 patients, 25.3%), renal impairment (10 patients, 13.3%), and night blindness (9 patients, 12%).
Note 5) 58 patients receiving JESELHY and 17 patients crossed-over to JESELHY.
Pharmacokinetics: The pharmacokinetic parameters of pimitespib following the repeated oral administration of 160 mg JESELHY once daily on an empty stomach in Japanese patients with advanced solid tumors (n=22) are shown in the table as follows. Following the repeated administration of 160 mg JESELHY once daily on an empty stomach, the accumulation rate of pimitespib at Day 5 was 1.27 times. (See Table 2.)

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Absorption: Effect of Food: Following a single oral administration of 160 mg JESELHY in Japanese patients with advanced solid tumors (n=16), the geometric mean ratios of C_max and AUC_inf of pimitespib in the fed state compared those in the fasted state were 1.92 and 1.64, respectively.
Distribution: The plasma protein binding ratio of pimitespib ranged 93.1%-93.6%. Pimitespib primarily bound to albumin fraction in the human plasma (in vitro). The blood-to-plasma concentration ratio of pimitespib ranged 0.525-0.630 in humans (in vitro).
Biotransformation: Pimitespib is primarily metabolized by CES1 (in vitro). Following the repeated oral administration of 150.5 mg/m² JESELHY to three patients with advanced solid tumors, unchanged pimitespib, an amide hydrolyzed product, and N-demethylated product were observed in the urine by 24 hours after administration.
Elimination: Following the oral administration of 107.5 mg/m² JESELHY to Japanese patients with advanced solid tumors (n=6), the urinary excretion rate of unchanged pimitespib was 2.2% of dose by 24 hours after administration.
Pharmacokinetics in special populations: No dedicated pharmacokinetics studies for elderly, liver and renal impairment was conducted at the moment.
Based on the results of population pharmacokinetics analysis, age, liver and renal function were found not to be predictors of pimitespib pharmacokinetics.
Toxicology: Preclinical safety data: General toxicity: Major toxicity target organs of pimitespib in the rats and dogs included the lymphohematopoietic tissue, hepatobiliary tissue, gastrointestinal tract, kidneys, adrenal glands, reproductive organs, skin, and bones. In dead and moribund animals, changes were also observed in the salivary glands, mammary glands, and trachea. The toxicities of pimitespib were observed in these organs at systemic exposures in the range of or below the anticipated human exposure level based on the unbound AUC comparison. In 4-week repeated oral dosing of pimitespib followed by a 4-week drug cessation, all these toxicity showed complete recovery or a tendency towards recovery in rats and dogs.
Impairment of Fertility: In a reproductive and developmental toxicity study, pimitespib exhibited growth inhibition effect, teratogenicity, and embryo-fetal lethality in rat embryo-fetus at the maternal toxic dosage. The no observed adverse effect level (NOAEL) was 2 mg/kg for dams and embryo-fetal development.
No specific studies on fertility have been performed. However, pimitespib induced increased apoptotic bodies in the vaginal epithelium, multifocal cysts in the ovaries, white patch in the ovary, decreased corpus luteum, and proliferation of interstitial gland in the repeated oral dose toxicity studies in rats. In addition, degeneration of the seminiferous tubule, atrophic changes of the accessory sex glands, and degeneration/necrosis of the germinal epithelium, accompanied by a decreased spermatozoa in the epididymis, were observed in rats or dogs. Therefore, a potential of pimitespib to adversely affect reproduction has to be considered.
Carcinogenicity: No carcinogenicity studies have been conducted.
Genotoxicity: In a reverse mutation test (Ames test), pimitespib had no effect. In contrast, in the chromosomal aberration test, the percentage of Chinese hamster lung cells (CHL/IU) with structural chromosome aberrations increased after 24 hours of treatment with pimitespib, indicating that pimitespib has clastogenic potential. In the bone marrow micronucleus test in rats, the percentage of reticulocytes with micronucleus increased at 30 mg/kg, indicating that pimitespib can induce micronuclei. Based on these results, pimitespib is considered to be genotoxic (structural chromosomal aberrations).
Environmental risk assessment (ERA): No environmental risk assessment studies have been conducted.

JESELHY is indicated for the treatment of gastrointestinal stromal tumor (GIST) that has progressed after cancer chemotherapy (including but not limited to Imatinib, Sunitinib, Regorafenib).

Posology: The recommended dosage of JESELHY is 160 mg of pimitespib administered orally once daily on an empty stomach for 5 consecutive days, followed by 2 days off, and repeated. When administered in the fed state, the C_max and AUC of JESELHY increase. To avoid food effects, JESELHY should not be taken between 1 hour before and 2 hours after a meal.
Dose adjustments for toxicity: If an adverse reaction occurs, treatment with JESELHY should be interrupted or the dose reduced according to symptoms and severity, taking into account the following criteria. (See Tables 3 and 4.)

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Click on icon to see table/diagram/image

Posology adjustments for special populations: None.
Method of administration: JESELHY is for oral administration.

There is limited clinical experience of an overdose with JESELHY.
There is no known antidote for JESELHY. In the event of overdose, the patient should be monitored for adverse events.

JESELHY is contraindicated in patients with a history of hypersensitivity to any of the ingredients of JESELHY.

Severe diarrhoea: In the JESELHY clinical program, there have been reports of serious renal disorders resulting from dehydration due to diarrhoea.
It is not possible to predict which patients will develop this event. Special attention should be paid to the symptom and consequences of diarrhoea, particularly dehydration and acute kidney injury. Antidiarrheal agents should be used as necessary. Electrolytes should be monitored carefully and fluid replacement considered in order to prevent dehydration and electrolyte shift. Dose modifications (interruption and/or reduction) should be applied as necessary.
Eye disorder: Eye disorder may occur.
Eye disorder should be closely monitored during administration. Efforts should be made to ensure early detection of ocular reactions, including an early ophthalmologic consultation in the event of any persistent or vision-reducing ocular symptoms. Dose interruption/dose reduction should be considered as necessary.
Haemorrhage: Serious ADRs of duodenal ulcer haemorrhage and intra-abdominal haemorrhage were reported.
It is not possible to predict which patients will develop this event. Special attention should be paid to the symptom of haemorrhage. Dose modifications (interruption and/or reduction) should be applied as necessary.
Effects on ability to drive and use machines: There was no report of the effects of JESELHY on the ability to drive or use machines from the studies that have been conducted so far.
Use in Pregnancy: Embryo-fetal toxicity: In an embryo-fetal development toxicity study in rats, growth inhibition, teratogenicity, and embryo-fetal lethality were observed in pregnant rats treated with 4 mg/kg of pimitespib. Although the plasma concentration of pimitespib in pregnant rats is unknown, the plasma concentration of unbound pimitespib at 4 mg/kg in non-pregnant female rats was 0.9-1.5 times and 0.6-1.0 times of that at the clinical therapeutic dose in terms of C_max and AUC, respectively. Therefore, it is possible that even the clinical therapeutic dose may affect embryos and fetuses. Genotoxicity studies showed that pimitespib induced chromosomal structural abnormalities, but did not induce mutagenicity or chromosomal numerical aberration.
There are no clinical data on embryo fetal toxicity from the clinical trials.
Since GIST progressed after chemotherapy has a poor prognosis and other treatment options are extremely limited, it is considered that it is acceptable to administer JESELHY with caution to pregnant women or women who may be pregnant, provided that the potential risks to the fetus are fully explained to the patient and her family, and only when the therapeutic benefits are judged to outweigh the risks.

Fertility: If JESELHY must be administered to a patient with reproductive potential, the possibility that JESELHY can decrease reproductive function should be considered. Animal studies (in rats) have reported increased apoptotic bodies in the vaginal epithelium, multifocal cysts in the ovaries, white patches in the ovaries, decreased corpora lutea, and proliferation of interstitial glands. In addition, animal studies (in rats and dogs) have reported degeneration of the seminiferous tubules, atrophic changes of the accessory sex glands, and degeneration/necrosis of the germinal epithelium, accompanied by decreased spermatozoa in the epididymis.
Pregnancy: Women of childbearing potential should be instructed to use appropriate contraception during treatment with JESELHY and for an appropriate period after the end of treatment.
In genotoxicity studies, JESELHY induced structural chromosomal aberrations. Men whose partner is of childbearing potential should be instructed to use appropriate contraception during treatment with pimitespib and for an appropriate period after the end of treatment.
Pregnant women or women who may be pregnant should be administered only when the therapeutic benefit is judged to outweigh the risk. An embryo-fetal development study in rats reported growth inhibition, teratogenicity, and embryonic death in embryos and fetuses at exposure doses below the clinical exposure dose (AUC).
Breast-feeding: It is advisable not to breastfeed while taking JESELHY. It may be excreted in human milk, and serious adverse reactions may occur in an infant with exposure to JESELHY through milk.

Tabulated list of adverse drug reactions: Table 5 shows the adverse drug reactions of JESELHY reported in the Blinded Administration Period and/or the Unblinded Administration period of Study 10058030. (See Table 5.)

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Post-Marketing Experience: There is post-marketing experience only in Japan, and it is limited.

No drug interaction studies have been conducted at the moment. The following information is based on results from in vitro studies and physiologically based pharmacokinetic (PBPK) simulations. Caution is advised if these drugs are given concomitantly.
Effect of other medications on pimitespib: P-gp and BCRP inhibitors or inducers: Pimitespib is a substrate of P-gp and BCRP (in vitro). P-gp and BCRP inhibitors or inducers may alter the concentration and activity of pimitespib.
Effect of pimitespib on other medications: CYP3A substrates: Pimitespib has a potential to time-dependently inhibit CYP3A (in vitro) and PBPK simulations suggested that midazolam concentration may be increased when used in combination of pimitespib.
MATE1 and MATE2-K substrates: Pimitespib has a potential to inhibit MATE1 and MATE2-K (in vitro) and PBPK simulations suggested that metformin concentration may be increased when used in combination of pimitespib.
P-gp, BCRP, and OATP1B1 substrates: Pimitespib has a potential to inhibit P-gp, BCRP, and OATP1B1 (in vitro). P-gp, BCRP, and OATP1B1 substrates concentration may be increased when used in combination of pimitespib.

Incompatibilities: Not applicable.
Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store at or below 30°C.
Shelf life: 24 months.

Cytotoxic Chemotherapy

L01X - OTHER ANTINEOPLASTIC AGENTS ; Used in the treatment of cancer.

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