Everolimus in Combination With Imatinib in Patients With Glivec Refractory/Resistant Gastrointestinal Stromal Tumors

Novartis

Status and phase: Completed; Phase 2; Phase 1

Conditions: Gastrointestinal Stromal Tumors

Treatments: Drug: Imatinib 800mg/day (Glevec is the brand name for imatinib); Drug: Imatinib 600mg/day (Glevec is the brand name for imatinib); Drug: RAD001

Study type: Interventional

Funder types: Industry

Identifiers

NCT01275222

CRAD001C2206

Details and patient eligibility

About

This trial was a Phase I/II, non-randomized, open label, multi-center study, following a sequential 2-part design.

Full description

The first part, Phase I, was designed to assess whether there is a pharmacokinetic interaction between Glivec/Gleevec (imatinib) and RAD001(everolimus) as well as to collect safety data when these two drugs are co-administered. The second part, (Phase II), was designed to assess the potential efficacy of the combination in imatinib-resistant GIST patients in two strata of patients:

• Patients resistant to imatinib as first-line drug therapy and in whom the maximum tolerated dose was at least 600 mg/d (Stratum 1, first-line resistant/refractory)
• Patients resistant to imatinib as well as to post-imatinib drug therapy (Stratum 2, post second-line therapy).

It was decided to discontinue the study and close to further enrollment based on alternative treatment options that became available. Phase 1 and Phase 2 Stratum 1 were ended early on 02-Nov-2006. Investigators were allowed to complete the enrollment in the Phase 2 Stratum 2.

Enrollment: 117 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

Phase l:

• Patients aged ≥ 18 years
• Patients with a histologically proven diagnosis of GIST and clinical evidence of resistance to imatinib despite at least 4 months continuous treatment with imatinib
• Patients with at least 2 months at a dosage of ≥ 600 mg/day (progression despite uninterrupted therapy for 2 months at ≥800 mg/d for patients entering the Phase I cohort investigating the 800 mg/d dose)
• Patients were to have at least one measurable lesion (longest diameter ≥20 mm on conventional CT or MRI scan
• patients were to have ≥10 mm on spiral CT) and were to have a WHO Performance Status Score ≤ 2.
• Patients also were to have adequate bone marrow, liver and renal function on imatinib treatment, as specified in the protocol

Phase ll:

• For Phase II (Stratum 2) patients must have progression on other 2nd line drug therapies following prior progression on imatinib (Stratum 2)

Exclusion criteria

• Women who are pregnant or breast-feeding
• Patients presenting with known or symptomatic CNS metastases or leptomeningeal involvement
• Patients with any concurrent major medical condition liable to compromise the patient's participation in the study (e.g. known HIV infection, uncontrolled diabetes, serious cardiac dysrhythmia or condition, New York Heart Association classification of III or IV, congestive cardiac failure, myocardial infarction with 6 months, unstable angina, chronic or acute renal or liver disease, uncontrolled infections including abscess or fistulae, etc.)
• Patients with a history of another malignancy within 5 years prior to study entry, except curatively treated non-melanotic skin cancer or in-situ cervical cancer
• Patients unwilling to or unable to comply with the protocol
• Patients who are receiving glucocorticoids (only if the p70s6 kinase1 assay is being performed), since these have been shown to inhibit p70s6 kinase1 activity.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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117 participants in 6 patient groups

Phase l: RAD001 20mg/week

Experimental group

Description:

RAD001 20 mg was given once a week.

Treatment:

Drug: RAD001

Phase l: RAD001 2.5mg/day + Glivec 600mg/day

Experimental group

Description:

RAD001 2.5 mg was given in combination with Glivec/Gleevec 600mg/day.

Treatment:

Drug: Imatinib 600mg/day (Glevec is the brand name for imatinib)

Drug: RAD001

Phase l: RAD001 5mg/day + Glivec 600mg/day

Experimental group

Description:

RAD001 5 mg was given in combination with Glivec/Gleevec 600mg/day.

Treatment:

Drug: Imatinib 600mg/day (Glevec is the brand name for imatinib)

Drug: RAD001

Phase l: RAD001 2.5mg/day + Glivec 800mg/day

Experimental group

Description:

RAD001 2.5 mg was given in combination with Glivec/Gleevec 800mg/day.

Treatment:

Drug: Imatinib 600mg/day (Glevec is the brand name for imatinib)

Drug: RAD001

Phase ll - Stratum l (first-line resistant/refractory): RAD001 2.5mg/day + Glivec 600mg/day

Experimental group

Description:

All first-line resistant/refractory patients received RAD001 2.5mg/day in combination with Glivec/Gleevec at a dose of 600mg/day.

Treatment:

Drug: RAD001

Drug: Imatinib 800mg/day (Glevec is the brand name for imatinib)

Phase ll - Stratum ll: (post second-line therapy): RAD001 2.5mg/day + Glivec 600mg/day

Experimental group

Description:

All post-second-line patients received RAD001 2.5mg/day in combination with Glivec/Gleevec at a dose of 600mg/day

Treatment:

Drug: RAD001

Drug: Imatinib 800mg/day (Glevec is the brand name for imatinib)