A Phase I Dose Escalation Study of CGM097 in Adult Patients With Selected Advanced Solid Tumors

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Solid Tumor With p53 Wild Type Status

Intervention / Treatment
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* Drug: CGM097


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CGM097 - Dose escalation<br> | Drug: CGM097<br>* Patients treated with CGM097<br>|
| Experimental: CGM097 - Dose Expansion at MTD or RP2D<br> | Drug: CGM097<br>* Patients treated with CGM097<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicities | To characterize the maximum tolerated dose (MTD) and/or identify the recommended dose for expansion(RDE) of CGM097. Dose Limiting Toxicities will be listed and their incidence summarized by primary system organ class, worst grade based on CTCAE version 4.03 and type of Adverse Event | From day 1 to day 28 of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic profile of CGM097 | Plasma concentration of CGM097 | At Cycle 1 Day 1, 2, 5, 8, 15 and 22, then each first day of the Cycle (28 days per Cycle) until discontinuation. | 
| Tumor response per RECIST | This includes duration of response and progression free survival | Baseline, then every third cycle (approximately every 12 weeks), until disease progression or discontinuation. | 
| Pharmacodynamic effect of CGM097 | Changes of tumors markers in tumor tissue and blood | At baseline, Cycle 2 Day 8 and at disease progression. | 
| Changes in laboratory values, vital signs or cardiac functionality, dose reduction, dose interruption and dose intensity, incidence and severity of adverse events. | Changes in laboratory values, vital signs or cardiac functionality, dose reduction, dose interruption and dose intensity, incidence and severity of adverse events. | 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). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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p53, solid tumor