Clinical trial NCT04200963: A Phase 1a/b Study of IK-175 as a Single Agent and in Combination With Nivolumab in Patients With Locally Advanced or Metastatic Solid Tumors and Urothelial Carcinoma
Official title: A Phase 1a/b, Open-Label, Dose-Escalation and Expansion Study of IK-175, an Oral Aryl Hydrocarbon Receptor (AHR) Inhibitor, as a Single Agent and in Combination With Nivolumab, a PD-1 Checkpoint Inhibitor in Patients With Locally Advanced or Metastatic Solid Tumors and Urothelial Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Urothelial Carcinoma
Urothelial Carcinoma Bladder
Bladder Cancer
Bladder Disease
Solid Tumor
Solid Carcinoma
Solid Tumor, Adult
Metastatic Cancer
Advanced Solid Tumor
Advanced Cancer
Metastatic Bladder Cancer
Metastatic Urothelial Carcinoma
Locally Advanced Solid Tumor
Neoplasms
Neoplasm Metastasis
Neoplasm Malignant
Neoplasm, Bladder
Urothelial Neoplasm
Neoplasm, Urinary Bladder
Bladder Neoplasm
Bladder Urothelial Carcinoma
Keywords: IK-175
KYN-175
Immunoncology
Aryl Hydrocarbon Receptor Inhibitor
AHRi
Aryl Hydrocarbon Receptor Antagonist
Antagonist
Inhibitor
anti-PD1
nivolumab
checkpoint inhibitor
CPI
aPDI
Lead sponsor: Ikena Oncology
Sponsor class: INDUSTRY
Collaborators: name: Bristol-Myers Squibb
First posted: 2019-12-16
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Dose escalation and expansion using the revised modified Toxicity Probability Interval (mTPI-2) design
Primary purpose: TREATMENT

Brief summary: This study will be conducted in adult subjects diagnosed with any form of an advanced or metastatic solid tumors including urothelial carcinoma for which standard therapy is no longer effective or is intolerable. This is a phase 1, multi-center, open label study designed to assess safety and tolerability of IK-175 as a single agent and in combination with nivolumab, to determine the recommended phase 2 dose (RP2D). Disease response, pharmacokinetics (PK), pharmacodynamics, and response biomarkers will also be assessed.


Eligibility criteria: Inclusion Criteria:

1. Adult patients ≥18 years of age.
2. Patients with confirmed solid tumors (including urothelial carcinoma) who have locally recurrent or metastatic disease that has progressed on or following all standard of care therapies or who is not a candidate for standard treatment.
3. For patients with urothelial carcinoma to be enrolled in the Combination Treatment arm, patients must have confirmation of urothelial carcinoma and have unresectable locally recurrent or metastatic disease that has progressed on or following all standard of care therapies, or who is not a candidate for standard treatment. Checkpoint inhibitor therapy with anti-PD-1 or anti-PD-L1 does not necessarily need to directly precede the study, but patients must have progressed on or within 3 months of receiving the last infusion/dose anti-PD-(L)1 therapy for inclusion in the Combination Treatment arm only.
4. Have measurable disease.
5. Accessible tumor that can be safely accessed for multiple core biopsies and patient is willing to provide tissue from newly obtain biopsies before and during treatment.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
7. Adequate organ function.
8. Highly effective birth control.
9. Time since the last dose of prior therapy to treat underlying malignancy (including other investigational therapy): 9a. Systemic cytotoxic chemotherapy: ≥ the duration of the most recent cycle of the previous regimen (with a minimum of 2 weeks for all, except 6 weeks for systemic nitrosourea or systemic mitomycin-C). 9b. Biologic therapy (eg, antibodies): ≥ 3 weeks or their dosing interval if shorter than 3 weeks (e.g. q2w therapy would require a 2-week washout). 9c. Small molecule therapies: ≥ 5 × half-life. 9d. Investigational Agent: ≥4 weeks or ≥5 × half-life, whichever is shorter

Exclusion Criteria:

1. Untreated symptomatic central nervous system (CNS) tumors or brain metastasis. Patients are eligible if CNS metastases are asymptomatic and do not require immediate treatment or have been treated and patients have neurologically returned to baseline (residual signs or symptoms related to the CNS treatment are permitted). In addition, patients must have been either off corticosteroids, or on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent) for at least 2 weeks prior to entering the Treatment period (Day 1).
2. Patients who have not recovered to ≤ Grade 1 or baseline from all adverse events (AEs) due to previous therapies
3. Has an active autoimmune disease that has required systemic treatment in past 2 years with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs; nonsteroidal anti-inflammatory drugs (NSAIDs) are permitted. Patients with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
4. Any condition requiring continuous systemic treatment with either corticosteroids (\>10mg daily prednisone equivalents) or other immunosuppressive medications within 2 weeks prior to first dose of study treatment (Inhaled or topical steroids and physiological replacement doses of up to 10 mg daily prednisone equivalent are permitted in the absence of active clinically significant \[ie, severe\] autoimmune disease.).
5. Any other concurrent antineoplastic treatment or investigational agent except for allowed local radiation of lesions for palliation and hormone ablation.
6. Uncontrolled or life-threatening symptomatic concomitant disease (including known symptomatic human immunodeficiency virus (HIV) positive with an AIDS defining opportunistic infection within the last year, or a current CD4 count \<350 cells/uL, symptomatic active hepatitis B or C checked at screening, or active tuberculosis). Patients with HIV are eligible if: 6a. they have received antiretroviral therapy (ART) for at least 4 weeks prior to entering the Treatment period as clinical indicated while enrolled on study; 6b. they continue on ART as clinically indicated while enrolled on study; 6c. CD4 counts and viral load are monitored per standard of care by a local health care provider.
7. Patients that have undergone a major surgery within 3 weeks of starting trial treatment or has inadequate healing or recovery from complications of surgery prior to starting trial treatment.
8. Prior radiotherapy within 2 weeks of start of study treatment. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had severe radiation pneumonitis. A 1-week washout is permitted for palliative radiation \[≤ 2 weeks of radiotherapy\] to non-CNS disease.
9. Prior AHR inhibitor treatment without Sponsor permission.
10. Potentially life-threatening second malignancy requiring systemic treatment within the last 3 years or which would impede evaluation of treatment response. Hormone ablation therapy is allowed within the last 3 years. Patients with history of prior early stage basal/squamous cell skin cancer or non-invasive or in situ cancers that have undergone definitive treatment at any time are eligible.
11. Recent or current significant cardiovascular disease (e.g. stroke, heart attack, heart failure, or arrhythmia).
12. Medical issue that limits oral ingestion or impairment of gastrointestinal function that is expected to significantly reduce the absorption of IK-175.
13. Clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke (\<6 months prior to enrollment), myocardial infarction (\<6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or the presence of any condition that can increase proarrhythmic risk (eg, hypokalemia, bradycardia, heart block) including any new, unstable, or serious cardiac arrhythmia requiring medication, or other baseline arrhythmia that might interfere with interpretation of ECGs on study (eg, bundle branch block). Patients with QTcF \>450 msec for males and \>470 msec for females on screening ECG are excluded. Any patients with a bundle branch block will be excluded with QTcF \>450 msec. Males who are on stable doses of concomitant medication with known prolongation of QTcF (eg, Selective Serotonin Reuptake Inhibitor Antidepressants) will only be excluded for QTcF \>470 msec.
14. History of life-threatening toxicity related to prior immune therapy (eg. anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (eg. hormone replacement after adrenal crisis).
15. Has an active infection requiring systemic therapy.
16. Treatment with any live/attenuated vaccine within 30 days of first study treatment.
17. A woman of child-bearing potential (WOCBP) who has a positive pregnancy test or is breastfeeding prior to treatment.

Primary outcomes:
measure: To determine the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD), and to characterize the dose-limiting toxicities (DLTs) of IK-175 as a single agent and in combination with nivolumab.
timeFrame: Approximately 6 months
measure: Safety and tolerability of IK-175 as a single agent and in combination with nivolumab including acute and chronic toxicities, in determining a recommended phase 2 dose (RP2D) of IK- 175.
timeFrame: Up to 100 days after the end of study treatment.
Secondary outcomes:
measure: Pharmacokinetics of IK-175: half-life (t1/2)
timeFrame: Days 1 and 2 of first 2 cycles (every 21 days), followed by Day 1 of every even cycle beginning with cycle 4 (every 42 days) through end of treatment (average of 4 months)
measure: Pharmacokinetics of IK-175: Maximum Serum Concentration (Cmax)
timeFrame: Days 1 and 2 of first 2 cycles (every 21 days), followed by Day 1 of every even cycle beginning with cycle 4 (every 42 days) through end of treatment (average of 4 months)
measure: Pharmacokinetics of IK-175: Area Under the Curve (AUC)
timeFrame: Days 1 and 2 of first 2 cycles (every 21 days), followed by Day 1 of every even cycle beginning with cycle 4 (every 42 days) through end of treatment (average of 4 months)
measure: Objective response rate (ORR) of IK-175 as a single agent and in combination with nivolumab
timeFrame: 12 months
measure: Progression-free survival (PFS) of IK-175 as a single agent and in combination with nivolumab
timeFrame: 12 months
measure: Duration of treatment (DOT) of IK-175 as a single agent and in combination with nivolumab
timeFrame: 12 months
measure: Duration of response (DOR) of IK-175 as a single agent and in combination with nivolumab
timeFrame: 12 months
measure: Disease control rate (DCR) of IK-175 as a single agent and in combination with nivolumab
timeFrame: 12 months
measure: Pharmacodynamic immune effects of IK-175 as a single agent and in combination with nivolumab on tumor-infiltrating cytotoxic T cells
timeFrame: Prior to Cycle 1 Day 1, and anytime between the end of Cycle 1 and end of Cycle 2. Each cycle is 21 days.
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner Health- MD Anderson Cancer Center
state: Arizona
city: Sarasota
country: United States
facility: Florida Cancer Specialists - Sarasota
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Kimmel Cancer Center
state: Maryland
city: Grand Rapids
country: United States
facility: START Midwest
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: Sydney Kimmel Cancer Center Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: The Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Ikena Oncology
name: Karim Malek, MD
role: STUDY_DIRECTOR
References: