Phase
Condition
Gliomas
Astrocytoma
Treatment
CM93
Clinical Study ID
Study Summary
Eligibility Criteria
Inclusion
Inclusion Criteria:
Have histologically confirmed recurrent or progressive World Health Organization IVisocitrate dehydrogenase (IDH) wild type glioblastoma and variants, includinghigh-grade astrocytoma with molecular features of glioblastoma (WHO grade IV).
Archival tumor from initial or other prior surgery is documented to have EGFRmutation or EGFR amplification
Previous first line therapy with at least radiotherapy utilizing standard dosing ofCNS radiation with or without chemotherapy.
Patients must have shown unequivocal evidence of tumor progression by MRI and haveconfirmed measurable disease per RANO criteria.
Patients must have confirmation of availability of sufficient tissue from priorsurgery revealing glioblastoma or variants for submission following registration forrepeat EGFR mutation testing and additional sequencing. The following amount oftissue is required:
1 formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred), or
20 FFPE unstained slides (5 µm thickness)
Patients must have recovered to grade 0 or 1 as determined by the National CancerInstitute CTCAE version 5.0 or pre-treatment baseline from clinically significanttoxic effects of prior therapy (including but not limited to exceptions foralopecia, laboratory values listed per inclusion criterion 3.1.12, and lymphopeniawhich is common after therapy with temozolomide).
An interval of at least 4 weeks (to registration) between prior surgical resectionor one week from stereotactic biopsy.
Age ≥18 years. Because no dosing or adverse event data are currently available onthe use of CM93 in participants <18 years of age, children are excluded from thisstudy, 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) (subjectswith Gilbert syndrome are allowed if direct bilirubin within normal limits)
AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN
creatinine ≤1.5mg/dL or a calculated creatinine clearance ≥60mL/min
negative serum beta-hCG test in women of childbearing potential (defined aswomen ≤50 years of age, or >50 years of age with a history of amenorrhea ≤12months prior to study entry).
Left ventricular ejection fraction (LVEF) at least 50% by echocardiogram ormultigated acquisition scan (MUGA).
Participants with known history or current symptoms of cardiac disease, or historyof treatment with cardiotoxic agents, should have a clinical risk assessment ofcardiac function using the New York Heart Association Functional Classification. Tobe eligible for this trial, participants should be class 2B or better.
The effects of CM93 on the developing human fetus are unknown. For that reason,women of childbearing age must agree to use dual contraceptive methods which, in theopinion of the principal investigator, are effective and adequate for that subject'scircumstances while on study drug and for 4 months afterward.
Men who partner with a woman of childbearing potential must agree to use effective,dual contraceptive methods (i.e., a condom, with female partner using oral,injectable or barrier method) while on study drug and for 4 months afterward.
Ability to understand and the willingness to sign a written informed consentdocument. Additional criteria for window-of-opportunity surgical cohort
Patients must be undergoing surgery for recurrent or progressive disease that isclinically indicated as determined by their care providers.
Ability of a neurosurgeon to gross or subtotally resect both enhancing andnon-enhancing components of the tumor and that sufficient tissue can be obtainedfrom each component for correlative studies.
Exclusion
Exclusion Criteria:
Prior evidence of IDH mutation by IHC or DNA sequencing (i.e., IDH wild typeonly)
Participants who have had prior treatment with any EGFR inhibitor, or VEGF orVEGFR 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, ortreatment with any cancer-directed systemic therapy less than 4 weeks or 5half-lives from study initiation, whichever is shorter.
Participants who have had any cancer-directed immunomodulatory ormolecularly-targeted agent or monoclonal antibody within 14 days prior toinitiation of study drug.
Participants who have used any investigational agents within 28 days or 5half-lives from study initiation, whichever is shorter.
For phase 1 dose escalation and dose expansion: increasing corticosteroidrequirement or a dose >6 mg per day of dexamethasone or equivalent dose ofother corticosteroids within 7 days prior to study initiation. This does notapply to patients in the window-of-opportunity surgical trial.
Participants who received radiation therapy within 12 weeks prior toregistration, unless there is surgical confirmation of recurrent disease orevidence of new enhancing recurrent disease outside of the prior radiotherapytreatment field.
Participants with major surgery within the last 28 days prior to registration.
History of allergic reactions attributed to compounds of similar chemical orbiologic composition to CM93.
Participants receiving any medications or substances that are strong inhibitorsof CYP3A4 (e.g., clarithromycin, azole antifungals, protease inhibitors,nefazadone, grapefruit juice) or those metabolized by CYP 3A4/3A5 areineligible. Caution is advised for participants taking dexamethasone as well asstrong inducer(s) of its metabolism. Because the lists of these agents areconstantly changing, it is important to regularly consult a frequently-updatedmedical reference. As part of the enrollment/informed consent procedures, theparticipant 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 participantis considering a new over-the-counter medicine or herbal product.
Participants with known human immunodeficiency virus or acquiredimmunodeficiency syndrome-related illness.
Participants with any of the following within 6 months prior to initiation ofstudy drug: uncontrolled congestive heart failure (New York Heart AssociationClassification 3 or 4), angina, myocardial infarction, cerebrovascularaccident, coronary/peripheral artery bypass graft surgery, transient ischemicattack.
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.
Evidence of Grade ≥ 2 intracranial hemorrhage.
Participants with any severe, acute, or chronic medical or psychiatriccondition, or laboratory abnormality that may increase the risk associated withstudy participation or study drug administration, may interfere with theinformed consent process and/or with compliance with the requirements of thestudy, or may interfere with the interpretation of study results and, in theInvestigator's opinion, would make the subject inappropriate for entry intothis study.
Participants with uncontrolled intercurrent illness, including active orclinically unstable bacterial, viral or fungal infection requiring systemictherapy.
Pregnant women are excluded from this study; there are no reproductive toxicitydata at the stage of development in animals. CM93 may have potential forteratogenic or abortifacient effects. Because there is an unknown but potentialrisk for adverse events in nursing infants secondary to treatment of the motherwith CM93, breastfeeding should be discontinued if the mother is treated withCM93.
Previous malignancy, except for non-squamous cell cancer of the skin orcarcinoma in situ of the uterine or cervix, unless the natural history ortreatment of the tumor does not interfere with the safety or efficacyassessment of the investigational regimen.
Participants with difficulty swallowing/unable to swallow pills; malabsorptionsyndrome; refractory nausea and vomiting, chronic gastrointestinal (GI) diseaseor previous significant bowel resection with clinically significant sequelaethat would preclude adequate absorption of study drug.
Additional criteria for window-of-opportunity surgical cohort
- Participants with >2 prior relapses of glioblastoma.