IRB Study Number 25-492
Status Recruiting
Phase Phase 1
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Primary Objectives
To determine the safety and tolerability and RDE of KQB168 as monotherapy and in combination with pembrolizumab
Secondary Objectives
To evaluate the efficacy of KQB168 as monotherapy and in combination with pembrolizumab
To evaluate the plasma PK of KQB168 alone and in combination with pembrolizumab
To determine a pharmacologically active dose (PAD) of KQB168
Exploratory Objectives
To evaluate pharmacodynamic biomarkers that correlate with outcome measures
Inclusion Criteria
Capable of giving signed informed consent as described in Section 10.3 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Participant must be at least 18 years of age at the time of signing the ICF.
Life expectancy of at least 3 months.
Locally advanced or metastatic disease which is not amenable to curative therapy and has progressed on or is intolerant to standard available therapy as deemed by the investigator.
Locally advanced/unresectable, recurrent or metastatic solid tumor that has progressed on immunotherapy, including immune checkpoint inhibitors (e.g., anti-PD-(L)1 therapy).
Histologically confirmed (cytological diagnosis is acceptable) diagnosis of head and neck cancer, non-small cell lung cancer, colorectal cancer, cervical cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, and clear cell renal cell carcinoma. Other tumor types may be considered following consultation with the medical monitor.
Measurable disease per RECIST v1.1 (see – Appendix 3).
Participants with previously treated brain metastases may participate provided the following:
o Radiographic stability (defined as brain imaging obtained at least 4 weeks after treatment of brain metastases showing no evidence of intracranial progression).
o Stable neurological symptoms (i.e., must have returned to baseline or resolved).
o Steroid dosing must be ≤ 15 mg prednisone or equivalent per day
Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 1).
Has adequate organ function as defined in Table 7.
Acute toxicities from any prior therapy, surgery, or radiotherapy must have resolved to Grade ≤ 1 as per the NCI-CTCAE v5.0, except for alopecia, Grade 2 platinum-induced peripheral neuropathy, and/or autoimmune endocrinopathies with stable endocrine replacement therapy.
A male participant is eligible to participate if they agree to the following during the study intervention period and for at least 6 months after (or the length directed by local guidelines, whichever is longer) the last dose of study intervention:
o Refrain from donating sperm;
AND
o Must agree to use contraception as detailed below in Appendix 2. Contraception use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
o Agree to use a male condom and consider female partner use of an additional highly effective contraceptive method with a failure rate of < 1% per year as described in Appendix 2 when having sexual intercourse with a woman of childbearing potential who is not currently pregnant. Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person.
- A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
o Is a woman of nonchildbearing potential (WONCBP) as defined in Appendix 2. OR
o Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), preferably with low user dependency, as described in Appendix 2 during the study intervention period and for at least 6 months after (or the length directed by local guidelines, whichever is longer) the last dose of study intervention. Contraception use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.
o A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) with 24 hours before the first dose of study intervention, see Section 8.5.6.
o Additional requirements for pregnancy testing during and after study intervention are located in Section 8.5.6.
o The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a women with an early undetected pregnancy.
- Female participants must not donate or retrieve for their own use, ova from the time of screening to 6 months (or the length directed by local guidelines, whichever is longer) after the last dose of study intervention.
Exclusion Criteria
Active primary CNS tumors and/or leptomeningeal metastases.
Other active malignancies within the last 2 years. Nonmelanoma skin cancers, localized malignancies treated with curative intent that have a minimal likelihood of recurrence as deemed by the investigator, and malignancies that do not require active systemic treatment (e.g., low risk chronic lymphocytic leukemia, endocrine therapy in breast cancer that is not treating active disease) may be eligible after discussion with the medical monitor or designee.
Recipients of allogeneic or autologous stem cell transplantation or organ transplantation.
History of significant hemoptysis or hemorrhage within 4 weeks of the first dose of study intervention.
Major surgery or significant traumatic injury within 4 weeks of first dose of study intervention or anticipation of the need for major surgery during study intervention.
History of intestinal disease, inflammatory bowel disease, major esophageal or gastric surgery, or other gastrointestinal conditions (e.g., uncontrolled nausea, vomiting, malabsorption syndrome) likely to alter absorption of study intervention or result in inability to swallow oral medications.
Significant cardiac disease:
a. New York Heart Association class III or IV congestive heart failure;
b. Unstable angina;
c. Myocardial infarction within the past 24 weeks;
d. Uncontrolled hypertension; or
e. Unstable cardiac arrhythmias.
Prolongation of QT/QTc interval defined as > 470 msec (average of triplicate screening measurements) using Frederica’s QT correction formula (QTcF) at Screening.
Current history of pneumonitis, interstitial lung disease, severe chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, other restrictive lung diseases, acute pulmonary embolism, or Grade ≥ 2 pleural effusion or ascites not controlled by tap or requiring indwelling catheters.
Any uncontrollable intercurrent illness, infection (including participants with active, symptomatic COVID-19 infections), or other conditions that could limit study compliance or interfere with assessments.
Exposure to any other investigational or commercial anti-cancer agents or therapies administered with the intention to treat malignancy within 14 days before the first dose administration.
Previous treatment with a PTPN inhibitor.
Use of systemic corticosteroids or other immunosuppressive therapy, concurrently or within 7 days of C1D1 of study drug(s), with the following exceptions:
a. Topical, intranasal, inhaled, ocular, intra-articular, and/or other nonsystemic corticosteroids.
b. Premedications required for CT or MRI scans.
c. Physiological doses of replacement steroid therapy (eg, for adrenal insufficiency). For example:
o Hydrocortisone: Up to 30 mg daily.
o Prednisone: Up to 15 mg daily.
o Dexamethasone: Up to 0.75 mg daily.
o Fludrocortisone: No limitation on use.
o Note: Replacement steroid above recommended physiological doses may be considered in discussion with the study sponsor and investigators based on the clinical need and will be handled on a case-by-case basis and documented accordingly.
Radiotherapy administered less than 21 days prior to the first dose of study medication or localized palliative radiotherapy administered less than 7 days prior to the first dose of study medication, or ongoing radiotherapy-induced toxicity of Grade 2 or greater based on NCI-CTCAE v5.0.
Known history of immune-mediated colitis, uncontrolled autoimmune disorders or other relevant congenital or acquired immunodeficiencies.
Active Hepatitis B virus (HBV) and/or Hepatitis C virus (HCV) infection. If hepatitis B surface antigen (HBsAg) is positive, quantitative HBV DNA must be undetectable to be eligible. If HCV antibody is positive, quantitative HCV RNA must be undetectable to be eligible.
Active HIV infection (i.e. participants with no detectable viral load for at least 1 month are permitted). HIV testing is not required for the screening unless required by the local health authorities.
Receipt of live attenuated vaccine within 14 days prior to the first dose of study intervention.
History of hypersensitivity to any component of KQB168 (all cohorts) or PD-1/L1 inhibitors (combination cohorts only).
Pregnant or breastfeeding.
