- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03290092
Trial of Taselisib in Overgrowth (TOTEM)
A Multi-Centre, Open Label, Single Arm, Phase IB/IIA, Trial of Taselisib (GDC0032) in PIK3CA-Related Overgrowth
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.
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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Angers, France, 49933
- CHU d'Angers
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Bordeaux, France, 33076
- CHU de Bordeaux - GH Pellegrin
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Dijon, France, 21000
- CHU Dijon Bourgogne
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Garches, France, 92380
- Hôpital Raymond Poincaré (AP-HP)
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Lille, France, 59037
- Hôpital Jeanne de Flandre
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Lyon, France
- HCL - Hôpital femme-mère-enfant
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Montpellier, France, 34295
- Hopital Saint Eloi
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Montpellier, France, 34090
- Hôpital Arnaud de Villeneuve
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Nantes, France, 44093
- Chu Hotel Dieu
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Nice, France, 06202
- CHU de Nice - Hôpital L'Archet 2
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Paris, France, 75743
- Hôpital Necker-Enfants Malades
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Rennes, France, 35203
- Hopital Sud
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Saint-Pierre, France, 97448
- CHU La Réunion - site GHSR
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Saint-Priest-en-Jarez, France, 42270
- CHU de Saint-Etienne Hôpital Nord
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Toulouse, France, 31059
- Hopital Larrey
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Tours, France, 37044
- Hopital Trousseau
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Vandoeuvre les nancy, France, 54511
- CHU de Nancy - Hopital de Brabois
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Vandœuvre-lès-Nancy, France, 54511
- Chu de Nancy
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment
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The first six participants cohort receive a starting dose of 1mg once daily of taselisib during four weeks.
The starting dose of the second cohort of 24 patients is 2 mg once daily.
This dose may be adjusted down according to the pharmacokinetic data or tolerability data derived from the first cohort.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Occurrence of dose limiting toxicities
Time Frame: less than 24 hours
|
The dose limiting toxicity (DLT) is defined as a Grade 3 or more AE using the National Cancer Institute (NCI). If two out of up to six participants at the same dose level experience a DLT as defined above, subsequent cohorts will be dosed at a lower level as illustrated in the flow-chart below. At least six evaluable participants are required to establish the MTD (Maximum tolerated dose) at a specific dose level for both combinations. |
less than 24 hours
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Collaborators and Investigators
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Other Study ID Numbers
- OLIVIER-FAIVRE ROCHE 2016
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on PIK3CA-Related Overgrowth
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Novartis PharmaceuticalsAvailablePIK3CA-Related Overgrowth Spectrum (PROS)
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Novartis PharmaceuticalsRecruitingPIK3CA-related Overgrowth Spectrum (PROS)United States, Canada, Spain, Switzerland, France, United Kingdom, Germany, Italy, China, Hong Kong, Netherlands, Norway
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Novartis PharmaceuticalsActive, not recruitingPIK3CA-related Overgrowth Spectrum (PROS)Spain, France, Ireland, United States
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Novartis PharmaceuticalsCompletedPIK3CA-Related Overgrowth Spectrum (PROS)Spain, France, Australia, United States, Ireland
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Novartis PharmaceuticalsRecruitingPIK3CA-related Overgrowth SpectrumUnited States
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National Human Genome Research Institute (NHGRI)CompletedGenetics | Growth Disorder | PIK3CA-Related Overgrowth Spectrum (PROS)United States
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Centre Hospitalier Universitaire DijonCompletedSegmental Overgrowth Disorders Due to PIK3CAFrance
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ArQule, Inc. (a wholly owned subsidiary of Merck...No longer availableGrowth Disorders | Proteus Syndrome | PIK3CA-Related Overgrowth Spectrum (PROS)
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National Human Genome Research Institute (NHGRI)Children's National Research Institute; Uniformed Services University of the...RecruitingProteus Syndrome | PIK3CA Related Overgrowth SpectrumUnited States
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Merck Sharp & Dohme LLCActive, not recruitingPIK3CA-Related Overgrowth Spectrum (PROS)/Proteus Syndrome (PS)United States, Australia, Brazil, Italy, United Kingdom
Clinical Trials on Taselisib (GDC0032)
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Southwest Oncology GroupNational Cancer Institute (NCI)CompletedRecurrent Squamous Cell Lung Carcinoma | Stage IV Squamous Cell Lung CarcinomaUnited States, Canada
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Vanderbilt-Ingram Cancer CenterNational Cancer Institute (NCI); Genentech, Inc.; Translational Breast Cancer... and other collaboratorsTerminatedStage IV Breast Cancer | Estrogen Receptor Negative | Estrogen Receptor Positive | HER2/Neu Negative | Progesterone Receptor Negative | Progesterone Receptor Positive | Triple-Negative Breast CarcinomaUnited States
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Centocor, Inc.Completed
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Royal Marsden NHS Foundation TrustPfizer; Roche Pharma AG; Institute of Cancer Research, United KingdomUnknownBreast Cancer | Advanced Solid TumoursUnited Kingdom
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Hoffmann-La RocheTerminatedBreast CancerItaly, United States, Korea, Republic of, Canada, Czechia, Spain, Australia, Bulgaria, China, Finland, France, Greece, Poland, Portugal, Taiwan, Thailand, Turkey, Colombia, Bosnia and Herzegovina, Mexico, Peru, Romania, Russian Federation and more
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Genentech, Inc.Breast International Group; SOLTI Breast Cancer Research Group; Austrian Breast...CompletedBreast CancerUnited States, United Kingdom, Germany, Australia, Austria, Belgium, Brazil, France, Guatemala, Italy, Korea, Republic of, Panama, Poland, Portugal, Spain, Czechia, Hungary, Mexico, Peru, Switzerland, El Salvador, Chile
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Otto Metzger, MDGenentech, Inc.Active, not recruitingMetastatic Breast Cancer | Recurrent Breast CancerUnited States
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SWOG Cancer Research NetworkNational Cancer Institute (NCI)CompletedRecurrent Squamous Cell Lung Carcinoma | Stage IV Squamous Cell Lung Carcinoma AJCC v7United States, Canada
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National Cancer Institute (NCI)Active, not recruitingGlioma | Hematopoietic and Lymphoid Cell Neoplasm | Melanoma | Lymphoma | Multiple Myeloma | Recurrent Ovarian Carcinoma | Breast Carcinoma | Recurrent Head and Neck Carcinoma | Recurrent Lung Carcinoma | Recurrent Skin Carcinoma | Gastric Carcinoma | Advanced Lymphoma | Advanced Malignant Solid Neoplasm | Refractory... and other conditionsUnited States, Puerto Rico, Guam