MC# 21-14 - A Phase I, open-label, multi-center, dose escalation and expansion study to evaluate safety, tolerability, pharmacokinetics, and anti-tumor activity of the WEE1 inhibitor IMP7068 monotherapy in patients with advanced solid tumors

  • Agent(s): IMP7068
  • Disease Type(s): Colorectal, Solid Tumor, Uterine Serous Carcinoma
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): WEE1

Mechanism of Action

IMP7068 is a small molecule inhibitor of WEE1, an enzyme involved in the checkpoint controlling the G2-M transition in cell cycle

Purpose

In this study, the sponsor and investigators want to learn:

  • About the safety and tolerability of IMP7068
  • How proteins that indicate the status of your disease are affected with use of IMP7068
  • If IMP7068 prevents or delays tumor growth or shrinks existing tumors
  • How much of IMP7068 is absorbed into the blood and how fast it is removed
Inclusion Criteria
  1. The patient must voluntarily participate in this clinical study. Be willing and able to provide written informed consent form (ICF) prior to any study activity
  2. Age ≥18 years on the day of signing the ICF (either from screening period for dose escalation stage or from pre-screening period for dose expansion stage), males or females
  3. In dose escalation stage, the enrolled patients must have histologically or cytologically confirmed advanced solid tumor that is refractory to standard treatment or for which no standard treatment exists.  The patients with known microsatellite-instability high (MSI-H) or deficient in mismatch repair (dMMR) disease are required to have received prior PD-1/PD-L1 therapy; those with known NTRK fusion are required to have received an approved TRK-inhibitor.  The patients who are suitable for resection or other localized therapy that is potentially curative are not eligible.
  4. In the dose expansion stage, patients with special tumor type and predictive biomarker(s) determined by central laboratory will be enrolled

Table 5: Cohort Specific Inclusion Criteria in Dose Expansion Stage

Cohort

Tumor Type

Inclusion Criteria

Cohort 1

Advanced CRC

  1. Patients have histological or cytological confirmed adenocarcinoma of the colon or rectum
  2. Patients had to have received locally and currently approved standard therapies* and to have disease progression during or after the last standard therapy or to have stopped standard therapy because of unacceptable toxicity.  Patients must have received an oxaliplatin-fluoropyrimidine doublet, an irinotecan-based regimen, and bevacizumab unless contraindicated.
  3. The patients who are suitable for resection or other localized therapy that is potentially curative are not eligible
  4. With TP53/KRAS double mutations

Cohort 2

Uterine serous carcinoma (USC)

  1. Female patients have histologically or cytologically confirmed uterine serous carcinoma.  Uterine carcinomas (with the exception of carcinosarcomas) that have any component that is considered serous will be considered a uterine serous carcinoma.
  2. Patients had to have received locally and currently approved standard therapies* and to have disease progression during or after the last standard therapy or to have stopped standard therapy because of unacceptable toxicity.
  3. The patients who are suitable for resection or other localized therapy that is potentially curative are not eligible
  4. With aberrant p53 expression

Cohort 3

Advanced non-CRC/non-

USC solid tumors

  1. Patients have histologically or cytologically confirmed non-CRC/non-USC solid tumors
  2. Patients had to have received locally and currently approved standard therapies* and to have disease progression during or after the last standard therapy or to have stopped standard therapy because of unacceptable toxicity
  3. The patients who are suitable for resection or other localized therapy that is potentially curative are not eligible
  4. With SETD2 deficiency

Cohort 4

Advanced non-CRC/non-

USC solid tumors

  1. Patients have histologically or cytologically confirmed non-CRC/non-USC solid tumors
  2. Patients had to have received locally and currently approved standard therapies* and to have disease progression during or after the last standard therapy or to have stopped standard therapy because of unacceptable toxicity
  3. The patients who are suitable for resection or other localized therapy that is potentially curative are not eligible
  4. With CCNE1 amplification

*Locally and currently approved standard therapies include PD-1/PD-L1 therapy for the patients with known microsatellite-instability high (MSI-H) or deficient in mismatch repair (dMMR) disease, and the approved TRK- inhibitor for patients with known NTRK fusion.

  1. Patients have measurable or non-measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.  For expansion part, patients should have measurable lesion (target lesions) at baseline.
  2. Patients have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 for dose escalation stage enrollment and ECOG performance status of 0 to 2 for dose expansion stage enrollment
  3. Patients have a life expectancy of at least 12 weeks
  4. Patients have adequate organ function, as indicated by the following laboratory values (had not received blood transfusion, apheresis infusion, erythropoietin, granulocyte colony- stimulating factor, and other relevant medical support within 14 days before the administration of IMP7068):

Table 6: Criteria for Laboratory Values of Adequate Organ Function

System

Laboratory Value

Hematological

Absolute neutrophil count (ANC)

≥1.5×109/L

Platelets

≥100×109/L

Hemoglobin

≥9 g/dL

Renal

 

Serum creatinine

Serum creatinine ≤1.5×upper limit of normal (ULN) or creatinine clearance ≥50 mL/min estimated using the Cockcroft-Gault equation

Hepatic

 

Total bilirubin

≤1.5×ULN (not applicable for patients with Gilbert’s syndrome, whose enrollment should be discussed with the sponsor).

Aspartate transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT)

≤2.5×ULN; for patients with liver metastases: ≤5×ULN

Coagulation

International normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT)

≤1.5×ULN; The INR applies only to patients who do not receive therapeutic anti-coagulation.

  1. Female patients should meet at least 1 of the following criteria before they can participate in the study:
    • Females who have no childbearing potential (i.e., physiologically incapable of pregnancy), including those who have undergone hysterectomy, bilateral oophorectomy, or bilateral salpingectomy
    • Post-menopausal (total cessation of menses for ≥1 year)
    • For those with childbearing potential, they should have a negative serum pregnancy test during the screening period (within 7 days prior to the first dose of IMP7068), should not be in lactation, and willing to take allowed contraceptive measure) throughout the study period, from signing the ICF (either from screening period for dose escalation stage or from pre-screening period for dose expansion stage) to 3 months after the last dose of IMP7068
  2. Male patients are eligible to participate in the study if they have undergone bilateral vasectomy or agree to use allowed methods of contraception and/or no donating sperms during the study period, from signing the ICF (either from screening period for dose escalation stage or from pre-screening period for dose expansion stage) to 3 months after the last dose of IMP7068
Exclusion Criteria
  1. Patients with active or untreated known CNS metastases and/or carcinomatous meningitis should be excluded.  However, patients with previously treated brain metastases may participate if they are clinically stable without steroids for at least 4 weeks prior to the first dose of IMP7068.  A mandatory radiographic imaging to confirm the absence of brain metastases at screening is not required.
  2. Patients with serious acute or chronic infections, including:
    • Patients with an uncontrolled acute infection, or an active infection requiring systemic treatment, or patients who have received systemic antibiotics within 7 days prior to the first dose of IMP7068;
    • Patients who have a known history of human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome.  Patients with unknown HIV infection status who are unwilling to undergo HIV testing should not be enrolled in the study;
    • Patients who have known active hepatitis B or C.  Patient with hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody positive test results during screening must be further tested for hepatitis B virus (HBV) DNA titer (excluding patients with a HBV DNA titer of more than 2000 IU/mL) and HCV RNA (excluding patients with an HCV RNA concentration exceeding the lower detection limit of the assay) to exclude active hepatitis B or hepatitis C infection requiring treatment.  Hepatitis B virus carriers, patients with stable hepatitis B infection after drug treatment (DNA titer not exceeding 2000 IU/mL) and HCV infected patients who received treatment and achieve sustained virologic response (SVR) for at least 12 weeks can be enrolled.
  3. Patients who have received prescription or non-prescription drugs or other products known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued 7 days prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of IMP7068.  Patients who have received phenobarbital/enzalutamide will require a 5-week washout prior to Day 1 of dosing.
  4. Patients who may need continuous treatment with proton pump inhibitors during the study period
  5. Patients who have received a live-virus vaccination within 28 days prior to the first dose of treatment
  6. Patients who are participating in or have participated in a study of an investigational agent and received study therapy or used an investigational device within 28 days of the first dose of treatment.  For investigational drugs, the washout period should be 5 half-lives or 28 days whichever is shorter.
  7. Patients have not recovered (i.e., to Grade ≤1 or to baseline, as evaluated by NCI-CTCAE Version 5.0) from prior anti-cancer therapy-induced AEs, except for alopecia
  8. Patients who have received chemotherapy, targeted therapy, immunotherapy, endocrine therapy (except for necessary androgen deprivation therapy [ADT with LHRH agonists/antagonist for metastatic castration resistant prostate cancer (mCRPC)]), anti- tumor Chinese herbal medicine or proprietary Chinese medicine treatment or other anti- cancer systemic treatment within 5 half-lives or 28 days (whichever is shorter) prior to the first dose of IMP7068.
  9. Patients who have undergone a major surgery or have undergone a radical radiotherapy within 28 days prior to the study treatment, or have undergone a palliative radiotherapy within 14 days prior to the study treatment, or have used a radioactive drug (Strontium, Samarium, etc.) within 56 days prior to the study treatment
  10. Patients who have other new malignancies within 2 years prior to the first dose of IMP7068 will be excluded, except for radically treated basal or squamous cell skin cancer.  Presence of other active invasive cancers will be excluded.  Patients with other malignancies that have been treated with no relapse within 2 years can be enrolled.
  11. Patients who have acute myocardial infarction, unstable angina, stroke, or transient ischemic attack within 6 months prior to the first dose of IMP7068; patients who have congestive heart failure (New York Heart Association [NYHA] Classification Class ≥II); patients who have severe arrhythmia requiring medication (including mean resting corrected QT interval (QTcF, using Fridericia’s formula, QTcF = QT/RR1/3) ≥450 msec for males and ≥470 msec for females in triplicate 12-lead ECG evaluation at screening, pacemaker installation, and previous diagnosis of congenital long QT syndrome)
  12. Patients who are unable to swallow oral medications.  Patients have gastrointestinal illnesses that may clinically significantly affect the absorption of oral medication IMP7068, e.g., ulcerative colitis, Crohn’s disease, chronic diarrhea with malabsorption, intractable nausea and vomiting, or have had a surgical procedure which could affect gastrointestinal absorption at discretion of investigators.
  13. Patients known to have a history of alcoholism or drug abuse within 2 years prior to the study treatment
  14. The patient who has any other medical or psychiatric condition that may interfere with the interpretation of study results, or is unable or unwilling to abide by the study protocol or cooperate fully with the investigator, in the judgment of the investigator, would be inappropriate for study participation

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/show/NCT04768868

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Re: MC# 21-14