CM93 Treatment in Subjects With Epidermal Growth Factor Receptor (EGFR)-Modified Recurrent Glioblastoma (rGBM)
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|ClinicalTrials.gov Identifier: NCT04933422|
Recruitment Status : Not yet recruiting
First Posted : June 21, 2021
Last Update Posted : June 21, 2021
|Condition or disease||Intervention/treatment||Phase|
|Glioblastoma||Drug: CM93||Phase 1|
CM93 is a third-generation, covalent/irreversible, brain penetrant small molecule Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor. It is not a substrate of p-glycoprotein or breast cancer resistance protein (bcrp) and is a mild inhibitor of bcrp. It is a potent inhibitor of EGFR mutations but also has activity against wild type EGFR.
This first-in-human phase I trial will evaluate the safety, tolerability, and pharmacokinetics (PK) of CM93 and determine the recommended Phase 2 dose (RP2D) for further evaluation using a 3+3 design (Part 1). Once the RP2D has been determined 12 additional patients will be treated in a dose expansion cohort to confirm the safety and tolerability of the selected dose (Part 2). Subsequent to the phase I trial a window-of-opportunity surgical trial will initiate. Tumor from both contrast enhancing and non-contrast enhancing areas of patients who received CM93 before surgery will be resected and evaluated to determine if therapeutic concentrations of the drug are achieved. Pharmacodynamic studies will be conducted in tumor tissue from patients who received CM93 before surgery and the patients who did not receive drug before surgery to determine if there is adequate inhibition of EGFR. After recovery from surgery all 30 patients will receive CM93 until progression, development of unacceptable toxicity, or withdrawal of consent and preliminary evidence of activity will be obtained.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||72 participants|
|Intervention Model:||Sequential Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase 1 Study Evaluating the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Effects of CM93 in Subjects With Recurrent Glioblastoma (rGBM) Characterized by Epidermal Growth Factor Receptor (EGFR) Mutation or Amplification|
|Estimated Study Start Date :||August 2021|
|Estimated Primary Completion Date :||July 2023|
|Estimated Study Completion Date :||July 2024|
Experimental: CM93 pre-treatment arm
Applicable only for part 3 of this trial (surgical window of opportunity), pre-treatment with CM93 prior to surgical resection of recurrent glioblastoma
oral capsule of CM93 administered once daily
Other Name: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide 4-methylbenzenesulfonate
No Intervention: No pre-treatment arm
Applicable only for part 3 of this trial (surgical window of opportunity), no pre-treatment prior to surgical resection of recurrent glioblastoma
- Dose-limiting toxicities [ Time Frame: 28 days ]Record and compare safety and tolerability, adverse events, changes in laboratory parameters and electrocardiogram measure of patients to baseline measurements. DLTs (dose-limiting toxicities) are defined as a clinically significant adverse event (AE) or laboratory abnormality unrelated to disease progression that meet certain criteria.
- Maximum tolerated dose [ Time Frame: 28 days ]The MTD (maximum tolerated dose) is defined as the highest dose level at which ≤1 of 6 subjects experience a DLT during Cycle 1 (the first 28 days of intervention).
- Recommended phase 2 dose [ Time Frame: 28 days ]
Determined by the DSMC (Data Safety Monitoring Committee) after review of safety data, the RP2D (recommended phase 2 dose) will be the MTD unless:
- Significant clinical anti-tumor effect (complete response, partial response, or stable disease for ≥2 months) is seen below the MTD, in which case a clinically active dose level may be selected as an RP2D; or
- Toxicities observed beyond Cycle 1 require reducing the RP2D(s) below the MTD level; or
- MTD is not achieved, in which case the highest dose level administered may become an RP2D.
- Concentration of CM93 in non-enhancing areas of tumor [ Time Frame: 7 days ]In part 3 of the study, tissue samples from non-enhancing areas of the tumor will be analyzed for CM93 and concentration will be reported for the CM93-treated group.
- Half-life of CM93 [ Time Frame: 22 days ]Calculate half-life from the plasma bioanalysis of CM93 and its active metabolite at different time points and doses.
- Maximum plasma concentration (Cmax) [ Time Frame: 22 days ]Calculate Cmax from the plasma bio analysis of CM93 and its active metabolite.
- Time to Maximum plasma concentration (Tmax) [ Time Frame: 22 days ]Calculate Tmax from the plasma bio analysis of CM93 and its active metabolite.
- Area under the curve (AUC) [ Time Frame: 22 days ]Calculate AUC from the plasma bio analysis of CM93 and its active metabolite.
- EGFR level in tumor specimens [ Time Frame: 7 days ]In part 3 of the study, average pEGFR (phosphorylated epidermal growth factor receptor) levels in the tumor specimens of CM93-treated surgical patients will be compared to the levels in tumor specimens from untreated patients and difference between the two groups noted.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04933422
|Contact: NeuroOnc Coordinator||617-632-2166||NeuroOnc_Coor@dfci.harvard.edu|
|Contact: Prem Das||781 248 firstname.lastname@example.org|