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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

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ClinicalTrials.gov Identifier: NCT04200963
Recruitment Status : Recruiting
First Posted : December 16, 2019
Last Update Posted : March 18, 2021
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Ikena Oncology

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.

Condition or disease Intervention/treatment Phase
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 Drug: IK-175 Drug: IK-175 and nivolumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 93 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Dose escalation and expansion using the revised modified Toxicity Probability Interval (mTPI-2) design
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 18, 2019
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : September 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: IK-175 Single Agent Dose Escalation
Approximately 5 dose escalation steps are planned during the Single Agent Treatment dose escalation phase of the study. (COMPLETE)
Drug: IK-175
Subjects will be administered IK-175 PO daily for every 21-day treatment cycle during the Single Agent Treatment dose escalation or for every 28-day treatment cycle during the Single Agent dose expansion.
Other Name: KYN-175

Experimental: IK-175 Single Agent Dose Expansion
A Single Agent Treatment dose expansion phase will be performed in patients with urothelial carcinoma with IK-175 after completion of the dose escalation to confirm the RP2D.
Drug: IK-175
Subjects will be administered IK-175 PO daily for every 21-day treatment cycle during the Single Agent Treatment dose escalation or for every 28-day treatment cycle during the Single Agent dose expansion.
Other Name: KYN-175

Experimental: IK-175 and nivolumab Combination Dose Escalation
Approximately 2 dose escalation steps are planned during the Combination Treatment dose escalation phase of the study.
Drug: IK-175 and nivolumab
Subjects will be administered IK-175 PO daily and administered a single dose of nivolumab IV on Day 1 for every 28-day treatment cycle during the Combination Treatment dose escalation and expansion.
Other Name: KYN-175 and nivolumab

Experimental: IK-175 and nivolumab Combination Dose Expansion
A Combination Treatment dose expansion phase will be performed in patients with urothelial carcinoma with IK-175 after completion of the dose escalation to confirm the RP2D.
Drug: IK-175 and nivolumab
Subjects will be administered IK-175 PO daily and administered a single dose of nivolumab IV on Day 1 for every 28-day treatment cycle during the Combination Treatment dose escalation and expansion.
Other Name: KYN-175 and nivolumab




Primary Outcome Measures :
  1. 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. [ Time Frame: Approximately 6 months ]
    Proportion of adverse events (AEs) meeting protocol-defined DLT criteria

  2. 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. [ Time Frame: Up to 100 days after the end of study treatment. ]
    Frequency of AEs overall, by grade, relationship to study treatment, time-of-onset, duration of the event, duration of resolution, and concomitant medications administered.


Secondary Outcome Measures :
  1. Pharmacokinetics of IK-175: half-life (t1/2) [ Time Frame: 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) ]
    Determine IK-175 half-life (t1/2).

  2. Pharmacokinetics of IK-175: Maximum Serum Concentration (Cmax) [ Time Frame: 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) ]
    Determine IK-175 Cmax

  3. Pharmacokinetics of IK-175: Area Under the Curve (AUC) [ Time Frame: 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) ]
    Determine IK-175 AUC

  4. Objective response rate (ORR) of IK-175 as a single agent and in combination with nivolumab [ Time Frame: 12 months ]
    Preliminary antitumor activity per RECIST 1.1 and assessment per immune Response Evaluation Criteria Solid Tumors (iRECIST) for subjects with urothelial carcinoma.

  5. Progression-free survival (PFS) of IK-175 as a single agent and in combination with nivolumab [ Time Frame: 12 months ]
    Preliminary antitumor activity per RECIST 1.1and assessment per immune Response Evaluation Criteria Solid Tumors (iRECIST) for subjects with urothelial carcinoma.

  6. Duration of treatment (DOT) of IK-175 as a single agent and in combination with nivolumab [ Time Frame: 12 months ]
    Preliminary antitumor activity per RECIST 1.1 and assessment per immune Response Evaluation Criteria Solid Tumors (iRECIST) for subjects with urothelial carcinoma.

  7. Duration of response (DOR) of IK-175 as a single agent and in combination with nivolumab [ Time Frame: 12 months ]
    Preliminary antitumor activity per RECIST 1.1 and assessment per immune Response Evaluation Criteria Solid Tumors (iRECIST) for subjects with urothelial carcinoma.

  8. Disease control rate (DCR) of IK-175 as a single agent and in combination with nivolumab [ Time Frame: 12 months ]
    Preliminary antitumor activity per RECIST 1.1 and assessment per immune Response Evaluation Criteria Solid Tumors (iRECIST) for subjects with urothelial carcinoma.

  9. Pharmacodynamic immune effects of IK-175 as a single agent and in combination with nivolumab on tumor-infiltrating cytotoxic T cells [ Time Frame: Prior to Cycle 1 Day 1, and anytime between the end of Cycle 1 and end of Cycle 2. Each cycle is 21 days. ]
    Characterization of tumor-infiltrating cytotoxic T cells in tumor biopsies collected before and during IK-175 treatment



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04200963


Contacts
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Contact: Marissa Timothy, MS 6033618939 mtimothy@ikenaoncology.com
Contact: Janine McDermott, MS 781 392 5556 jmcdermott@ikenaoncology.com

Locations
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United States, Michigan
START Midwest Recruiting
Grand Rapids, Michigan, United States, 49546
Contact: Nehal Lakhani    616-954-5554    yvette.cole@startmidwest.com   
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: David Aggen, MD    646-628-0118    aggend@mskcc.org   
United States, Pennsylvania
Sydney Kimmel Cancer Center Thomas Jefferson University Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Babar Bashir, MD    215-955-6000    mtimothy@ikenaoncology.com   
UPMC Hillman Cancer Center Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Jason Luke, MD, FACP    412-647-2811    mientkiewiczk@upmc.edu   
United States, Tennessee
The Sarah Cannon Research Institute Recruiting
Nashville, Tennessee, United States, 37203
Contact: Meredith A McKean, MD    615-329-7274    Diana.CatalanNavarro@SarahCannon.com   
Sponsors and Collaborators
Ikena Oncology
Bristol-Myers Squibb
Investigators
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Study Director: Jason Sager, MD Ikena Oncology
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Responsible Party: Ikena Oncology
ClinicalTrials.gov Identifier: NCT04200963    
Other Study ID Numbers: IK175-001
KYN-175 ( Other Identifier: Ikena Oncology )
First Posted: December 16, 2019    Key Record Dates
Last Update Posted: March 18, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ikena Oncology:
IK-175
KYN-175
Immunoncology
Aryl Hydrocarbon Receptor Inhibitor
AHRi
Aryl Hydrocarbon Receptor Antagonist
Antagonist
Inhibitor
anti-PD1
nivolumab
checkpoint inhibitor
CPI
aPDI
Additional relevant MeSH terms:
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Carcinoma
Neoplasms
Neoplasm Metastasis
Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Urinary Bladder Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplastic Processes
Pathologic Processes
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urologic Diseases
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents