Study of the CHK1 Inhibitor BBI-355, an ecDNA-directed Therapy (ecDTx), and the RNR Inhibitor BBI-825, in Subjects With Tumors With Oncogene Amplifications

NCT05827614 | Active Not Recruiting Phase 1 FDA Drug

• 1 other identifier: BBI-355-101
• Study Type: interventional
• Target: 85
• Locations: 1 country
• Sites: 16

Brief Summary

BBI-355 is an oral, potent, selective checkpoint kinase 1 (or CHK1) small molecule inhibitor in development as an ecDNA (extrachromosomal DNA) directed therapy (ecDTx). BBI-825 is an oral, potent, selective ribonucleotide reductase (or RNR) small molecule inhibitor. This is a first-in-human, open-label, 2-part, Phase 1/2 study to determine the safety profile and identify the maximum tolerated dose and recommended Phase 2 dose of BBI-355 administered as a single agent or in combination with BBI-825 or other select therapies.

Conditions

Triple Negative Breast Cancer (TNBC); High Grade Serous Ovarian Carcinoma; High Grade Endometrial Carcinoma; Anogenital Cancer; Head and Neck (HNSCC); Cutaneous Squamous Cell Carcinoma (CSCC); Cervical Squamous Cell Carcinoma; ER+ Breast Cancer; Leiomyosarcoma (LMS); Undifferentiated Pleomorphic Sarcoma (UPS); Pancreatic Cancer Metastatic; Small Cell Lung Cancer

Keywords

ecDNA; extrachromosomal DNA; Amplification; Oncogene Amplification; Checkpoint kinase 1; CHK1; RNR; ribonucleotide reductase

Outcome Measures

Primary Outcomes (2)

• Frequency and severity of treatment emergent adverse events (TEAEs) of BBI-355 as a single agent and in combination with each of the following agents: erlotinib, futibatinib, or BBI-825

  TEAEs will be assessed and severity assigned by using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.

  Start of Cycle 1 until 30 days following last dose (each cycle is 28 days)

• Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of BBI-355 as a single agent and in combination with erlotinib, futibatinib, or BBI-825

  The MTD and/or RP2D of BBI-355 as a single agent and in combination with erlotinib, futibatinib, or BBI-825 will be determined.

  Start of Cycle 1 until 30 days following last dose (each cycle is 28 days)

Secondary Outcomes (5)

• Maximum observed plasma concentration (Cmax) of BBI-355, erlotinib, futibatinib, and BBI-825

  Start of Cycle 1 until Day 1 of last treatment cycle (each cycle is 28 days)

• Trough observed plasma concentration (Ctrough) of BBI-355, erlotinib, futibatinib, and BBI-825

  Start of Cycle 1 until Day 1 of last treatment cycle (each cycle is 28 days)

• Time to Cmax (Tmax) of BBI-355, erlotinib, futibatinib, and BBI-825

  Start of Cycle 1 until Day 1 of last treatment cycle (each cycle is 28 days)

• Area under the concentration time curve (AUC) of BBI-355, erlotinib, futibatinib, and BBI-825

  Start of Cycle 1 until Day 1 of last treatment cycle (each cycle is 28 days)

• Anti-tumor activity of BBI-355 as a single agent and in combination with erlotinib, futibatinib, or BBI-825

  1-2 years: Start of Cycle 1 until documented disease progression or death (each cycle is 28 days)

Study Arms (5)

Single Agent Dose Escalation

EXPERIMENTAL

Single agent BBI-355, administered orally in 28-day cycles

Drug: BBI-355

Single Agent Dose Expansion

EXPERIMENTAL

Single agent BBI-355, administered orally in 28-day cycles

Drug: BBI-355

Dose Escalation in Combination with EGFR Inhibitor

EXPERIMENTAL

Combination therapy of BBI-355 and EGFR inhibitor erlotinib, administered orally in 28-day cycles.

Drug: BBI-355; Drug: Erlotinib

Dose Escalation in Combination with FGFR Inhibitor

EXPERIMENTAL

Combination therapy of BBI-355 and FGFR1-4 inhibitor futibatinib, administered orally in 28-day cycles.

Drug: BBI-355; Drug: Futibatinib

Dose Escalation in Combination with RNR Inhibitor

EXPERIMENTAL

Combination therapy of BBI-355 and RNR Inhibitor BBI-825, administered orally in 28-day cycles.

Drug: BBI-355; Drug: BBI-825

Interventions

BBI-355 DRUG

Oral CHK1 inhibitor

Dose Escalation in Combination with EGFR Inhibitor; Dose Escalation in Combination with FGFR Inhibitor; Dose Escalation in Combination with RNR Inhibitor; Single Agent Dose Escalation; Single Agent Dose Expansion

Erlotinib DRUG

EGFR Inhibitor

Dose Escalation in Combination with EGFR Inhibitor

Futibatinib DRUG

FGFR1-4 Inhibitor

Dose Escalation in Combination with FGFR Inhibitor

BBI-825 DRUG

Oral RNR Inhibitor

Dose Escalation in Combination with RNR Inhibitor

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Locally advanced or metastatic non-resectable solid tumors, whose disease has progressed despite all standard therapies or for whom no further standard or clinically acceptable therapy exists,
• Evidence of oncogene amplification,
• Availability of FFPE tumor tissue, archival or newly obtained,
• Measurable disease as defined by RECIST Version 1.1,
• Adequate hematologic function,
• Adequate hepatic and renal function,
• Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1,

You may not qualify if:

• Single agent arm: Prior exposure to CHK1 or WEE1 inhibitors,
• BBI-355 combination with BBI-825 arm: Prior exposure to combination therapy of any RNR inhibitor plus CHK1/2 inhibitor,
• Hematologic malignancies,
• Primary CNS malignancy, leptomeningeal disease, or symptomatic active CNS metastases, with exceptions per study protocol,
• Prior or concurrent malignancies, with exceptions per study protocol,
• History of HBV, HCV, or HIV infection,
• Clinically significant cardiac condition,
• Active or history of interstitial lung disease (ILD) or pneumonitis, or history of ILD or pneumonitis requiring steroids or other immunosuppressive medications,
• QTcF \> 470 msec,
• Prior organ allograft transplantations or allogeneic peripheral blood stem cell/bone marrow transplantation,

Sponsors & Collaborators

• Boundless Bio, Inc.: lead

Study Sites (16)

UCLA Medical Center

Los Angeles, California, 90095, United States

Location

Sarcoma Oncology

Santa Monica, California, 90403, United States

Location

HealthONE

Denver, Colorado, 80218, United States

Location

Florida Cancer Specialists

Lake Mary, Florida, 32746, United States

Location

The University of Kansas

Fairway, Kansas, 66205, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

START Midwest

Grand Rapids, Michigan, 49546, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

SCRI Oncology Partners

Nashville, Tennessee, 37203, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77054, United States

Location

NEXT Oncology - Dallas

Irving, Texas, 75039, United States

Location

NEXT Oncology

San Antonio, Texas, 78229, United States

Location

NEXT Oncology

Fairfax, Virginia, 22031, United States

Location

University of Washington, Fred Hutchinson Cancer Center

Seattle, Washington, 98109, United States

Location

University of Wisconsin

Madison, Wisconsin, 53792, United States

Location

Related Publications (7)

• Jones R, Plummer R, Moreno V, Carter L, Roda D, Garralda E, Kristeleit R, Sarker D, Arkenau T, Roxburgh P, Walter HS, Blagden S, Anthoney A, Klencke BJ, Kowalski MM, Banerji U. A Phase I/II Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination with Low-Dose Gemcitabine in Patients with Advanced Cancer. Clin Cancer Res. 2023 Jan 17;29(2):331-340. doi: 10.1158/1078-0432.CCR-22-2074.

  PMID: 36378548 BACKGROUND

• Italiano A, Infante JR, Shapiro GI, Moore KN, LoRusso PM, Hamilton E, Cousin S, Toulmonde M, Postel-Vinay S, Tolaney S, Blackwood EM, Mahrus S, Peale FV, Lu X, Moein A, Epler J, DuPree K, Tagen M, Murray ER, Schutzman JL, Lauchle JO, Hollebecque A, Soria JC. Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors. Ann Oncol. 2018 May 1;29(5):1304-1311. doi: 10.1093/annonc/mdy076.

  PMID: 29788155 BACKGROUND

• Tang J, Weiser NE, Wang G, Chowdhry S, Curtis EJ, Zhao Y, Wong IT, Marinov GK, Li R, Hanoian P, Tse E, Mojica SG, Hansen R, Plum J, Steffy A, Milutinovic S, Meyer ST, Luebeck J, Wang Y, Zhang S, Altemose N, Curtis C, Greenleaf WJ, Bafna V, Benkovic SJ, Pinkerton AB, Kasibhatla S, Hassig CA, Mischel PS, Chang HY. Enhancing transcription-replication conflict targets ecDNA-positive cancers. Nature. 2024 Nov;635(8037):210-218. doi: 10.1038/s41586-024-07802-5. Epub 2024 Nov 6.

  PMID: 39506153 BACKGROUND

• Wu S, Bafna V, Chang HY, Mischel PS. Extrachromosomal DNA: An Emerging Hallmark in Human Cancer. Annu Rev Pathol. 2022 Jan 24;17:367-386. doi: 10.1146/annurev-pathmechdis-051821-114223. Epub 2021 Nov 9.

  PMID: 34752712 BACKGROUND

• Turner KM, Deshpande V, Beyter D, Koga T, Rusert J, Lee C, Li B, Arden K, Ren B, Nathanson DA, Kornblum HI, Taylor MD, Kaushal S, Cavenee WK, Wechsler-Reya R, Furnari FB, Vandenberg SR, Rao PN, Wahl GM, Bafna V, Mischel PS. Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature. 2017 Mar 2;543(7643):122-125. doi: 10.1038/nature21356. Epub 2017 Feb 8.

  PMID: 28178237 BACKGROUND

• Lange JT, Rose JC, Chen CY, Pichugin Y, Xie L, Tang J, Hung KL, Yost KE, Shi Q, Erb ML, Rajkumar U, Wu S, Taschner-Mandl S, Bernkopf M, Swanton C, Liu Z, Huang W, Chang HY, Bafna V, Henssen AG, Werner B, Mischel PS. The evolutionary dynamics of extrachromosomal DNA in human cancers. Nat Genet. 2022 Oct;54(10):1527-1533. doi: 10.1038/s41588-022-01177-x. Epub 2022 Sep 19.

  PMID: 36123406 BACKGROUND

• Kim H, Nguyen NP, Turner K, Wu S, Gujar AD, Luebeck J, Liu J, Deshpande V, Rajkumar U, Namburi S, Amin SB, Yi E, Menghi F, Schulte JH, Henssen AG, Chang HY, Beck CR, Mischel PS, Bafna V, Verhaak RGW. Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers. Nat Genet. 2020 Sep;52(9):891-897. doi: 10.1038/s41588-020-0678-2. Epub 2020 Aug 17.

  PMID: 32807987 BACKGROUND

MeSH Terms

Conditions

Triple Negative Breast Neoplasms; Squamous Cell Carcinoma of Head and Neck; Leiomyosarcoma; Histiocytoma, Malignant Fibrous; Small Cell Lung Carcinoma

Interventions

Erlotinib Hydrochloride; futibatinib

Condition Hierarchy (Ancestors)

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Muscle Tissue; Neoplasms, Connective and Soft Tissue; Sarcoma; Histiocytoma; Neoplasms, Fibrous Tissue; Neoplasms, Connective Tissue; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Robert Doebele, MD, PhD

  Boundless Bio, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: BBI-355 single agent dose escalation and expansion, and BBI-355 dose escalation in combination with select targeted therapies.

Study Record Dates

• First Submitted: March 27, 2023
• First Posted: April 25, 2023
• Study Start: March 24, 2023
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): March 31, 2027
• Last Updated: January 23, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (16)