Safety and Effectiveness of ABM-168 in Adults With Advanced Solid Tumors

M
Mateusz Opyrchal, MD, PhD

Primary Investigator

Administratively Closed
18 years or above
All
Phase 1
112 participants needed
2 Locations

Brief description of study

What is the purpose of this study?
This is a Phase 1, First-in-Human (FIH), open-label, multicenter, dose escalation and doseudy to evaluate the safety, tolerability, pharmacokinetics and preliminaryumor activity of ABM-168 in adult patients with RAS or RAF or NF-1 mutated advancedd tumors as ABM-168 may have a significant effect in inhibiting cell growth.

THIS STUDY IS ENROLLING BY INVITATION ONLY - Consistent with most oncology trials, patients are not actively “recruited,” but are screened by their physician for appropriate clinical trial(s) at the time of their routine clinic visit. Occasionally, a patient may be a self-referral or physician referral, but are still screened for appropriate clinical trials at the time of their routine clinic visit. PI and staff may send copies of relevant consent forms to these patients to look over prior to actually consenting or enrolling them. This may take place at the patient's visit at which the consent is presented or the patient's next visit to the outpatient hematology/oncology clinic.

Interested in participating? For more information about this research study or other cancer-related clinical trials at IU Simon Comprehensive Cancer Center, please contact:
IU Clinical Trials Office 
Phone: (317) 278-5632

Detailed description of study

What will happen during the study?
This is a First-in-Human (FIH), open-label, multicenter, dose escalation and dose expansion, Phase I study of ABM-168, for the treatment of advanced solid tumors in adult patients.
The study consists of two parts:
Part A: Dose escalation. The starting dose of ABM-168 is 0.5 mq po qd, and dose escalation will be guided by a "3+3" design. ABM-168 will be administered once daily on a continuoushedule. Each treatment cycle consists of 28 days.
Part B: Dose Expansion. Expansion will be conducted in the adult patients with advanced solidumors that carry either RAS, RAF or NF-1 mutations. There are two cohorts for Dose: Patients will be enrolled into either Dose Expansion Cohort 1 (EX1) or DoseCohort 2 (EX2).
  • Cohort EX1: Patients enrolled will have preferred indications (i.e., melanoma, colonung cancer, and pancreatic carcinoma) who had confirmed RAS, RAF or NF-1utations and measurable lesion(s) at the beginning of the study. Patients withurable brain lesions(s) which have metastasized are highly preferred.
  • Cohort EX2: Patients enrolled will have primary CNS (Central Nervous System tumors withd RAS, RAF or NF-1 mutations.
Dose limiting toxicity (DLT) will be evaluated and managed per the pre-defined DLT criteriad rules specified in the protocol. MTD (Maximum Tolerated Dose) and/or RP2D will be determined based on the totality of safety, clinical pharmacokinetics, and efficacy data fromvaluable patients enrolled and in treated in both dose escalation cohorts and dosehorts. The RP2D (recommended phase II dose) could be the MTD, or alternatively a dose recommended by the SMC (Safety Monitoring Committee) if no MTD is determined in the dosed/or dose expansion.

Eligibility of study

You may be eligible for this study if you meet the following criteria:

  • Conditions: Advanced Solid Tumor, RAS Mutation, RAF Mutation, NF1 Mutation
  • Age: 18 years or above
  • Gender: All

Inclusion Criteria:
  1. Male and female subjects age 18 years and older who are able to sign informed consentd comply with the protocol
  2. Patients with histologically or cytologically documented, locally advanced, ord tumor malignancy that has either:
    1. failed prior standard therapy; or
    2. exhausted all existing standard therapy; or
    3. standard therapy is not considered appropriate per subject and/or investigator.he lines of previous standard therapy received.
  3. Patients with asymptomatic or symptomatic but stable brain metastases or CNS primary
    malignancies who meet following criteria specifically:
    • Asymptomatic, brain metastases or primary CNS tumors;
    • Stable symptomatic brain metastases or CNS primary tumors not requiring steroidsving steroids treatment (dexamethasone or equivalent) withdaily dosage no more than 4 mg, with a stable or reduced dosage of steroidswithin 2 weeks prior to the planned first dose
  4. ECOG performance score of 0 or 1, or Karnofsky performance score of ≥ 70.
  5. ≥ 3 months life expectancy
  6. Receiving no blood transfusions or granulocyte colony-stimulating factor (G-CSF) orher hematopoietic stimulating factors within 2 weeks prior to the planned firstdosing. Adequate organ function confirmed at screening as evidenced by:
    • Absolute Neutrophil Count (ANC) ≥ 1.5 × 10^9/L
    • Hemoglobin (Hgb) ≥ 90 g/dL
    • Platelets (Plt) ≥ 75 ×10^9/L
    • AST/ALT ≤ 2.5 × Upper Limit of Normal (ULN) or ≤ 5.0 × ULN if liver metastases
    • Total bilirubin ≤ 1.5 × ULN, or direct bilirubin < ULN (for patients with totalbilirubin levels >1.5 ×ULN)
    • Calculated creatinine clearance ≥ 60 mL/min
    • International normalized ratio (INR) and activated partial thromboplastin time(APTT) ≤ 1.5 × ULN, if received no anti-coagulation medication(s); INR ) ≤ ULN,ved anti-coagulation medication(s).
    • Average QTcF ≤ 470 ms per Fridericia formula
  7. Negative Hepatitis B Surface Antigen (HBsAg) at screening, or positive HBsAg with HBV
    DNA below LLN.
    Notes: Manage HBsAg positive subject according to the institutional standard practices(i.e., monitor HBV DNA, prescribe anti-HBV therapy as needed, etc.)
  8. Hepatitis C Virus (HCV) viral load below limit of quantification at screening, orve HCV antibody with negative HCV-RNA.
    Notes: Only conduct HCV antibody and/or HCV-RNA assay in the subjects with priorhistory of HCV infection.
  9. Negative HIV at screening, or patients with prior history of HIV infection, CD4+T-cell (CD4+) counts ≥ 350 cells/μL and without a history of AIDS-definingunistic infections.
  10. Negative serum pregnancy test within 72 hours before starting study treatment in allusal women and women < 12 months after the onset of menopause
  11. Must agree to take sufficient contraceptive methods to avoid pregnancy, starting fromhe consent until 3 months post receiving the last dose of study drug
  12. Able to swallow capsule as a whole
  13. [Dose Escalation Cohorts Only] Subject with evaluable but not measurable lesion iswed for enrollment.
  14. [Dose Expansion Cohorts Only] Subject must have at least one measurable lesion,detected at the baseline assessment by RECIST V1.1d tumors or the RANO criteria for primary CNS tumors, such asgliomas.
    • The lesion(s) exposed to previous radiation cannot be selected as target(s) at baseline assessment, unless obvious progression of the lesion(s) canbe proved via the imaging assessment;
    • For solid tumor brain metastases lesions:
    • If the longest diameter of the measurable intracranial lesion is < 0.5 cm, thenurable lesion should exist [Dose Expansion cohortsy];
    • Measurable brain lesions that are 0.5 - 3 cm in longest diameter as defined byhe modified RECIST V1.1 criteria are allowed.
    • Brain lesion size > 3 cm is not eligible
Exclusion Criteria:
  1. Women who are pregnant or breast-feeding.
  2. Have leptomeningeal disease (LMD).
  3. Have a history of stroke within 6 months prior to the first dose.
  4. Have impaired cardiac function or clinically significant cardiovascular disease(s)uding but not limited to any of the following:
    • Left ventricular ejection fraction (LVEF) < 50% as determined by cardiacultrasound.
    • Congenital long QT syndrome.
    • Grade 2 type II AV block or grade 3 AV block.
    • Unstable angina within 6 months prior to the first dose.
    • Acute myocardial infarction within 6 months prior to the first dose.
    • ≥ Class III heart failure per New York Heart Association (NYHA) functionalwithin 6 months prior to the first dose.
    • ≥ CTCAE Grade 2 ventricular arrhythmia within 6 months prior to study initiation.
  5. Have uncontrolled hypertension at screening, with systolic blood pressure > 160 mmHg
    or diastolic blood pressure > 100 mmHg after receiving anti-hypertension treatment.
  6. Have unresolved ≥ CTCAE Grade 2 diarrhea at the time of the first dose; or havegastrointestinal impairment conditions or diseases that significantly alter ABM-168bsorption at screening per investigator (e.g., ulcerative disease, poorly controlledusea, vomiting, malabsorption syndrome, or small intestine dissection)
  7. Have ≥ CTCAE Grade 2 eye diseases at screening, such as conjunctival mixed cellularulcer.
  8. Have severe chronic or active infection requiring intravenous antibiotic treatment(s)within 2 weeks prior to the first dose, including but not limited to hospitalizationdue to infection complications, bacteremia, severe pneumonia or active tuberculosis.
    • Subjects with topical fungal infection of the skin or nails are eligible forudy enrollment.
    • Subjects receiving prophylactic antibiotics (e.g., to prevent urinary tractbations of chronic obstructive pulmonary disease), except forhe antibiotics prohibited per protocol, are eligible for study enrollment.
  9. Received solid organ or hematopoietic bone marrow/stem cell transplantation within 5
    years prior to the screening.
  10. Received chemotherapy, targeted therapy or immunotherapy within 4 weeks prior to thedose, except for fluorouracil or small molecule target therapy.
    Notes: Fluorouracil or small molecule target therapy received within five half-life or2 weeks (whichever is longer) prior to the first dose is not allowed.
  11. Received anti-tumor Chinese herbal medicines or proprietary Chinese medicines within 2weeks prior to the first dose.
  12. Received extensive prior radiotherapy to more than 30% of bone marrow reserves; orved Whole Brain Radiation Therapy (WBRT) within 4 weeks prior to the first dose;ved palliative radiotherapy for non-target lesions (e.g., bone radiotherapy), including stereotactic body radiotherapy (SBRT) and stereotacticdiosurgery (SRS) within 2 weeks prior to the first dose.
  13. Have adverse reactions related to previous anti-tumor therapy that have not recovered≤ CTCAE Grade 1 or previous baseline at screening.
    Notes: Subjects with alopecia, or ≤ CTCAE Grade 2 peripheral neuropathy, orhypothyroidism stabilized by hormone replacement therapy, etc. are allowed for the.
  14. Have undergone major surgery within 4 weeks prior to the first dose, or have notvered from the side effects of major surgery, or expect to receive major surgeryduring study treatment.
    Notes: For subject who has recovered from major surgery per investigator, a minimum of2 weeks washout between the major surgery and the first dose is required.
  15. Received therapeutic doses of warfarin sodium or any other coumarin derivativegulant at screening.
  16. Received systemic corticosteroids within 2 weeks prior to the first dose, or notvered from adverse effects of previous corticosteroids treatment, except those asdescribed in the inclusion criteria for subjects with brain metastases.
    Notes: Subjects who received topical, intranasal or inhaled glucocorticoids; orubjects who received physiologic dose of steroids for adrenal replacement; subjectswho received single-use glucocorticoids for the prevention of contrast medium allergyhe imaging enhancement examinations are eligible for study enrollment.
  17. Have history of alcohol abuse or alcohol addiction within 3 months prior to the firstdose.
  18. Have known, documented, or suspected history of substance abuse, except for opioids. prescribed for pain relief.
  19. Have past or current evidence of conditions that may affect the study results pervestigator, or any conditions, treatment or laboratory abnormalities that maywith the subject's participation in the trial and study compliance.
  20. Other severe and/or poorly controlled concomitant diseases that may cause unacceptabley risks or affect compliance with the study protocol.
  21. History of immunodeficiency, including a positive HIV antibody test.
  22. Other circumstances deemed as not suitable for study enrollment per investigator.

Updated on 13 Dec 2024. Study ID: ABM168X1101, CTO-ABM168X1101, 18599

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