Trial of Taselisib in Overgrowth (TOTEM)

University Hospital Center (CHU) Dijon Bourgogne

Status and phase

Terminated

Phase 2

Phase 1

Conditions

PIK3CA-Related Overgrowth

Treatments

Drug: Taselisib (GDC0032)

Study type

Interventional

Funder types

Other

Identifiers

NCT03290092

OLIVIER-FAIVRE ROCHE 2016

Details and patient eligibility

About

Segmental overgrowth disorders are rare conditions characterised by abnormal growth which is usually asymmetric and confined to discrete parts of the body. We and others have identified mosaic activating mutations in the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K; encoded by the PIK3CA gene) in a subset of overgrowth disorders. The PI3K-AKT-mTOR is a critical signalling pathway, which regulates cellular growth, proliferation and survival. Activating mutations in PIK3CA lead to increased activation of the PI3K-AKT-mTORC1 axis, which in turn promotes excessive growth in affected tissue.

The PIK3CA-related overgrowth spectrum is wide, and depends upon the timing of the founder mutation in embryogenesis, and potentially upon the exact mutation. Clinical presentation ranges from isolated enlargement of a digit, to extensive overgrowth of limbs, abdomen and in some cases the brain, and may be accompanied by vascular or lymphatic malformations. Associated morbidity can be profound, with functional impairment, debilitating haemorrhages and thromboses, coupled with neurological sequelae and, in some cases, death. At present, serial debulking surgery is the only available therapeutic option.

The identification of gain-of-function mutations in PI3K has raised the possibility of treatment with drugs that inhibit PIK3CA (the p110 alpha catalytic subunit of PI3K). Taselisib is a selective inhibitor of class I PI3Ks and has direct inhibitory activity of the p110α isoform with a Kiapp value of 0.29 nmol/l.

Enrollment

19 patients

Sex

All

Ages

16 to 65 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Have given, or their legal representative has given, written informed consent to participate
Aged 16 years to 65 years inclusive
Male or female
Post-zygotic PIK3CA mutation
Clinically stable in the opinion of the investigator
Participant Pregnancy and contraception:

o Female participants of child bearing potential must use an effective method of contraception during treatment and for at least 3 months after the final dose of taselisib. Acceptable methods are:
True abstinence (this must be the participant's usual and preferred lifestyle, not just for the duration of the trial)
Oral contraceptive (either combined or progestogen alone)
Contraceptive implant, injections or patches
Vaginal ring
Intrauterine device (IUD, coil or intrauterine system)
Condom and cap
Diaphragm plus spermicide
- A female participant of child bearing potential is defined as a sexually mature woman not surgically sterilized or not post-menopausal for at least 12 consecutive months if aged 55 years or older.
- Men must use one of the following, reliable forms to contraception for the entire duration of treatment and for 3 months after the final dose of taselisib:
Condom plus spermicide even if female partner is using another method of contraception (Men should also use a condom to protect male partners, or female partners who are pregnant or breast feeding, from exposure to the Trial medicine in semen).
True abstinence (this must be the participant's usual and preferred lifestyle, not just for the duration of the Trial)

Exclusion criteria

Pregnant or breastfeeding
HIV infection
Hypersensitivity to taselisib or any of its excipients
Any current medical disorder or medication likely to impair ability to follow the trial protocol safely and effectively
Are concurrently taking an mTOR inhibitor or any other small molecule inhibitor of the PI3K-AKT signalling pathway
Unable or unwilling to give informed consent
Sirolimus or taselisib treatment in 12 weeks prior to screening
Treatment with a strong inducer or inhibitor of CYP3A4 without the possibility to stop this medication within the week prior to the screening. This includes:
Macrolide Antibiotics: clarithromycin, telithromycin, erythromycin, troleandomycin
Gastrointestinal prokinetic agents: metoclopramide.
Antifungals: itraconazole, ketoconazole, fluconazole, voriconazole, clotrimazole
Calcium channel blockers: verapamil, diltiazem, nicardipine
Grapefruit containing foods/drinks
Anticonvulsants: carbamazepine, phenobarbital, phenytoin
Antibiotics: rifampicin, rifabutin, rifapentine
Herbal preparations: St. John's wort (Hypericum perforatum). Other drugs: bromocriptine, cimetidine, danazol, cyclosporine, lansoprazole, calcium containing antacids.
Inability to attend trial visits
If less than 3 months post- major surgery at screening
Any past medical history of inflammatory bowel disease or chronic diarrhoea of unknown aetiology
History of type 1 or type 2 diabetes mellitus requiring insulin, GLP-1 analogues or oral hypoglycaemic agents.
History of inflammatory bowel disease, ischemic colitis, or colitis of unknown origin.
Fasting blood glucose > 6.9 mmol/l
HbA1C > 6%
Long QT, congenital or acquired
Active pneumonitis
Patients who require daily supplemental oxygen
Inadequate renal function defined as creatinine clearance or radioisotope GFR < 60ml/min/1.73 m²
Inadequate liver function defined as:
Total bilirubin > 2.0 x ULN or conjugated bilirubin > 2.0 x ULN for age, and
SGPT (ALT) or SGOT (AST) ≥ 1.5 x ULN for age, and
Serum albumin < 30 g/L
Inadequate fasting LDL cholesterol > 4.2 mmol/l
Deprived of freedom by an administrative or court order, or benefiting from a system of legal protection (tutorship, curatorship or safeguard of justice).
Not covered by health insurance