Clinical trial NCT01760525: A Phase I Dose Escalation Study of CGM097 in Adult Patients With Selected Advanced Solid Tumors
Official title: A Phase I, Open-label, Multi-center, Dose Escalation Study of Oral CGM097, a p53/HDM2-interaction Inhibitor, in Adult Patients With Selected Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumor With p53 Wild Type Status
Keywords: p53, solid tumor
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-01-04
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a first in human phase I study of single agent CGM097 in patients with advanced solid tumors who have progressed despite standard therapy or for whom no standard therapy exists. The tumor must be characterized by p53wt status. The study consists of a dose escalation part where patients will receive escalating doses of CGM097, and a dose expansion part in which patients are given CGM097 at the maximum tolerated dose (MTD) or Recommended Phase 2 Dose (RP2D). Each dose escalation step will be decided based on the recommendation from an adaptive Bayesian logistic regression model (BLRM).

Detailed description: This is a multi-center, open-label, dose finding, phase I study of single agent CGM097, administered in patients with advanced solid tumors who have progressed despite standard therapy or for whom no standard therapy exists. Patients' tumors must be characterized by p53wt status.

The study consists of a dose escalation part, where cohorts of three to six newly enrolled patients will receive escalating doses of CGM097, and a dose expansion part, in which patients are given CGM097 the maximum tolerated dose (MTD) or Recommended Phase 2 Dose (RP2D). Novartis and the site investigators will jointly decide on each dose escalation step based on the recommendation from an adaptive Bayesian logistic regression model (BLRM). If safety data should indicate a lower increment than suggested by the BLRM, the next dose level (DL) will be adjusted accordingly.

Eligibility criteria: Inclusion Criteria:

* Patient has advanced solid malignancy that has progressed despite standard therapy, or for which no effective standard therapy exists
* Tumor of the patient is p53wt
* Evaluable disease as determined by RECIST 1.1
* WHO performance status 0-2

Exclusion criteria:

* Prior treatment with CGM097 or other p53/HDM2-interaction inhibitor
* Patient with symptomatic or growing CNS metastatic lesions
* Concurrent other malignancy
* Clinically significant cardiac disease as defined in the protocol
* Diagnosis of acute or chronic pancreatitis
* Concomitant therapy that precludes enrollment, as defined in the protocol
* Women of child-bearing potential, unless they are using highly effective methods of contraception during dosing and for 2 weeks after study drug discontinuation
* Pregnant or nursing women

Other protocol-defined inclusion/exclusion criteria may apply.

Primary outcomes:
measure: Incidence of Dose Limiting Toxicities
timeFrame: From day 1 to day 28 of treatment
Secondary outcomes:
measure: Pharmacokinetic profile of CGM097
timeFrame: At Cycle 1 Day 1, 2, 5, 8, 15 and 22, then each first day of the Cycle (28 days per Cycle) until discontinuation.
measure: Tumor response per RECIST
timeFrame: Baseline, then every third cycle (approximately every 12 weeks), until disease progression or discontinuation.
measure: Pharmacodynamic effect of CGM097
timeFrame: At baseline, Cycle 2 Day 8 and at disease progression.
measure: Changes in laboratory values, vital signs or cardiac functionality, dose reduction, dose interruption and dose intensity, incidence and severity of adverse events.
timeFrame: At Cycle 1 Day 1, 2, 5, 8, 15, 22 and 28, Cycle 2 Day 1, 8,15 and 22, then each Day 1 and 15 of the Cycle until discontinuation. For dose interruption, dose intensity and adverse events: each day of the Cycle until discontinuation (28 days per Cycle).
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Institute SC (2)
state: Massachusetts
city: Lyon Cedex
country: France
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Bauer S, Demetri GD, Halilovic E, Dummer R, Meille C, Tan DSW, Guerreiro N, Jullion A, Ferretti S, Jeay S, Van Bree L, Hourcade-Potelleret F, Wuerthner JU, Fabre C, Cassier PA. Pharmacokinetic-pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies. Br J Cancer. 2021 Aug;125(5):687-698. doi: 10.1038/s41416-021-01444-4. Epub 2021 Jun 17.