CM93 Treatment in Subjects With Epidermal Growth Factor Receptor (EGFR)-Modified Recurrent Glioblastoma (rGBM)

NCT04933422 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: CM93-101
• Study Type: interventional
• Target: 72
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a first-in-human study of CM93, an oral investigational drug, in adults with Epidermal Growth Factor Receptor-modified glioblastoma. The study is designed in three parts consisting of a dose-escalation phase, a dose-expansion phase and a window-of-opportunity surgical trial. The trial objectives are to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical effects of CM93 in this patient population.

Conditions

Glioblastoma

Keywords

EGFR; rGBM; EGFR-altered rGBM

Outcome Measures

Primary Outcomes (4)

• Dose-limiting toxicities

  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.

  28 days

• Maximum tolerated dose

  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).

  28 days

• Recommended phase 2 dose

  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.

  28 days

• Concentration of CM93 in non-enhancing areas of tumor

  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.

  7 days

Secondary Outcomes (5)

• Half-life of CM93

  22 days

• Maximum plasma concentration (Cmax)

  22 days

• Time to Maximum plasma concentration (Tmax)

  22 days

• Area under the curve (AUC)

  22 days

• EGFR level in tumor specimens

  7 days

Study Arms (2)

CM93 pre-treatment arm

EXPERIMENTAL

Applicable only for part 3 of this trial (surgical window of opportunity), pre-treatment with CM93 prior to surgical resection of recurrent glioblastoma

Drug: CM93

No pre-treatment arm

NO INTERVENTION

Applicable only for part 3 of this trial (surgical window of opportunity), no pre-treatment prior to surgical resection of recurrent glioblastoma

Interventions

CM93 DRUG

oral capsule of CM93 administered once daily

Also known as: 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

CM93 pre-treatment arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have histologically confirmed recurrent or progressive World Health Organization IV isocitrate dehydrogenase (IDH) wild type glioblastoma and variants, including high-grade astrocytoma with molecular features of glioblastoma (WHO grade IV).
• Archival tumor from initial or other prior surgery is documented to have EGFR mutation or EGFR amplification
• Previous first line therapy with at least radiotherapy utilizing standard dosing of CNS radiation with or without chemotherapy.
• Patients must have shown unequivocal evidence of tumor progression by MRI and have confirmed measurable disease per RANO criteria.
• Patients must have confirmation of availability of sufficient tissue from prior surgery revealing glioblastoma or variants for submission following registration for repeat EGFR mutation testing and additional sequencing. The following amount of tissue is required:
• formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred), or
• FFPE unstained slides (5 µm thickness)
• An interval of at least 4 weeks (to registration) between prior surgical resection or one week from stereotactic biopsy.
• Age ≥18 years. Because no dosing or adverse event data are currently available on the use of CM93 in participants \<18 years of age, children are excluded from this study, but will may be eligible for future pediatric trials.
• Karnofsky performance status ≥ 60 (Appendix A).
• Participants must have adequate organ and marrow function as defined below:
• absolute neutrophil count ≥1,500/mcL
• hemoglobin ≥ 9g/dL
• platelets ≥100,000/mcL
• total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (subjects with Gilbert syndrome are allowed if direct bilirubin within normal limits)

You may not qualify if:

• \. Prior evidence of IDH mutation by IHC or DNA sequencing (i.e., IDH wild type only)
• \. Participants who have had prior treatment with any EGFR inhibitor, or VEGF or VEGFR inhibitor.
• \. Participants who have had temozolomide less than 23 days from study initiation, treatment with CCNU or BCNU less than 42 days from study initiation, or treatment with any cancer-directed systemic therapy less than 4 weeks or 5 half-lives from study initiation, whichever is shorter.
• \. Participants who have had any cancer-directed immunomodulatory or molecularly-targeted agent or monoclonal antibody within 14 days prior to initiation of study drug.
• \. Participants who have used any investigational agents within 28 days or 5 half-lives from study initiation, whichever is shorter.
• \. For phase 1 dose escalation and dose expansion: increasing corticosteroid requirement or a dose \>6 mg per day of dexamethasone or equivalent dose of other corticosteroids within 7 days prior to study initiation. This does not apply to patients in the window-of-opportunity surgical trial.
• \. Participants who received radiation therapy within 12 weeks prior to registration, unless there is surgical confirmation of recurrent disease or evidence of new enhancing recurrent disease outside of the prior radiotherapy treatment field.
• \. Participants with major surgery within the last 28 days prior to registration.
• \. History of allergic reactions attributed to compounds of similar chemical or biologic composition to CM93.
• \. Participants receiving any medications or substances that are strong inhibitors of CYP3A4 (e.g., clarithromycin, azole antifungals, protease inhibitors, nefazadone, grapefruit juice) or those metabolized by CYP 3A4/3A5 are ineligible. Caution is advised for participants taking dexamethasone as well as strong inducer(s) of its metabolism. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
• \. Participants with known human immunodeficiency virus or acquired immunodeficiency syndrome-related illness.
• \. Participants with any of the following within 6 months prior to initiation of study drug: uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4), angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack.
• \. Pulmonary embolism within 1 month prior to initiation of study drug.
• \. Unstable cardiac dysrhythmias or persistent prolongation of the QTc (Fridericia) interval to \>450msec for males or \>470msec for females.
• \. Any contraindication to contrast-enhanced MRI examination.

Sponsors & Collaborators

• Crimson Biopharm Inc.: lead

MeSH Terms

Conditions

Glioblastoma

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Central Study Contacts

NeuroOnc Coordinator

CONTACT

617-632-2166; NeuroOnc_Coor@dfci.harvard.edu

Prem Das

CONTACT

781 248 5699; prem.das@crimson-bio.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 24, 2021
• First Posted: June 21, 2021
• Study Start (Estimated): January 1, 2027
• Primary Completion (Estimated): July 1, 2029
• Study Completion (Estimated): July 1, 2029
• Last Updated: August 21, 2024

Record last verified: 2024-08