Phase 1b/2 Study of TTI-101 in Combination for Patients With Metastatic Hormone Receptor-Positive and HER2-Negative Breast Cancer

NCT05384119 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: TVD-101-002B5R01CA255960
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 6

Brief Summary

The primary objective of Phase 1b will be to evaluate the safety and tolerability of TTI-101 when added to palbociclib and AI or fulvestrant administered orally to participants with hormone receptor-positive (HR+) human epidermal receptor 2-negative (HER2)- palbociclib-resistant breast cancer, and to determine the recommended Phase 2 dose (RP2D) for TTI-101 when added to palbociclib and AI or fulvestrant. The primary objective of Phase 2 will be to evaluate anti-tumor activity in participants who receive TTI-101 added to palbociclib or ribociclib and AI or fulvestrant.

Conditions

Breast Cancer

Keywords

Breast cancer; HR+ HER2-, palbociclib-resistant breast cancer; TTI-101; STAT3 Inhibitor; Palbociclib; Aromatase inhibitor; ribociclib; fulvestrant

Outcome Measures

Primary Outcomes (4)

• Phase 1b: Number of Participants Who Experience a Dose Limiting Toxicity (DLT)

  Number of Participants Who Experience a Dose Limiting Toxicity (DLT)

  Day 1 to Day 28

• Phase 1b: Number of Participants Who Experience an Adverse Event (AE)

  An AE is any untoward medical occurrence in a participant or clinical study participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. Any clinically significant changes between baseline and postbaseline laboratory assessments, electrocardiograms (ECGs), vital signs and physical examinations were recorded as AEs.

  Up to approximately 17 months

• Phase 1b: Number of Participants Who Experience a Serious Adverse Event (SAE)

  Number of Participants Who Experience a Serious Adverse Event (SAE)

  Up to approximately 17 months

• Phase 2: Landmark Progression Free Survival at 6 Months (PFS6)

  Landmark Progression Free Survival at 6 Months (PFS6)

  6 months

Secondary Outcomes (14)

• Phase 1b: PFS6

  6 months

• Phase 1b and Phase 2: Clinical Benefit Rate (CBR)

  Up to approximately 17 months

• Phase 1b and Phase 2: Overall Response Rate (ORR)

  Up to approximately 17 months

• Phase 1b and Phase 2: Overall Response Rate (ORR)

  Up to approximately 17 months

• Phase 1b and Phase 2: Maximum Observed Plasma Concentration (Cmax) of TTI-101

  Cycle 2 Day 1 (cycle is 28 days)

Study Arms (2)

Phase 1b: Dose Escalation

EXPERIMENTAL

Participants will receive up to 3 dose levels of TTI-101 added to palbociclib and AI or fulvestrant to determine the RP2D.

Drug: TTI-101; Drug: Palbociclib; Drug: Aromatase inhibitor (AI); Drug: fulvestrant

Phase 2: Dose Expansion

EXPERIMENTAL

Enrollment in Phase 2 may commence with approval from the safety review committee. Participants will be enrolled and treated at the RP2D of TTI-101 added to palbociclib or ribociclib and AI or fulvestrant.

Drug: TTI-101; Drug: Palbociclib; Drug: Aromatase inhibitor (AI); Drug: fulvestrant; Drug: ribociclib

Interventions

TTI-101 DRUG

Oral tablet

Phase 1b: Dose Escalation; Phase 2: Dose Expansion

Palbociclib DRUG

Oral capsule

Also known as: Ibrance ®

Phase 1b: Dose Escalation; Phase 2: Dose Expansion

Aromatase inhibitor (AI) DRUG

Oral tablet

Phase 1b: Dose Escalation; Phase 2: Dose Expansion

fulvestrant DRUG

Oral tablet

Phase 1b: Dose Escalation; Phase 2: Dose Expansion

ribociclib DRUG

Oral tablet

Phase 2: Dose Expansion

Eligibility Criteria

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

You may qualify if:

• Participants must meet all the following criteria to be eligible:
• Age ≥18 years at the time of informed consent.
• Metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy.
• For Phase 1b,currently receiving palbociclib and AI or fulvestrant; for Phase 2, currently receiving palbociclib or ribociclib and AI or fulvistrant therapy in the metastatic setting with evidence of progressive disease. In addition:
• Must have remained on palbociclib or ribociclib and AI or fulvestrant therapy for ≥6 months for advanced breast cancer or metastatic disease prior to evidence of progression that in the opinion of the treating physician warrants continued therapy with palbociclib or ribociclib and AI or fulvestrant.
• Dosage of palbociclib, ribociclib, AI and fulvestrant must remain unchanged from regimen prior to study enrollment specifically palbociclib at a dose of 125, 100, or 75 mg administered orally for 21 days every 28-day cycle or ribociclib at a dose of 200, 400, or 600 mg administered orally for 21 days every 28-day cycle.
• All men and premenopausal women must be on medical gonadal suppression therapy with a gonadotropin analog (e.g, goserelin or leuprolide) and have estrogen levels in the postmenopausal range by institutional criteria at baseline.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Has documented confirmation of histological or cytological HR-positive, HER2-negative breast cancer per local laboratory testing.
• Up to 2 prior lines of systemic treatment (most recent line of therapy must be palbociclib and AI or fulvestrant for Phase 1b and palbociclib or ribociclib and AI or fulvestrant for Phase 2) in the locally advanced or metastatic setting is allowed; the participant must have shown evidence of progressive disease on palbociclib and AI or fulvestrant for Phase 1b and palbociclib or ribociclib and AI or fulvestrant for Phase 2 in the locally advanced or metastatic setting prior to enrollment.
• Willing to provide a representative fresh tumor tissue specimen prior to enrollment. The fresh tumor specimen must be obtained after evidence of progression on palbociclib and AI or fulvestrant for Phase 1b and palbociclib or ribociclib and AI or fulvestrant for Phase 2.
• Participants with bone only disease WITHOUT a soft tissue component, may opt out of the tumor biopsy.
• The presence of measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 is preferred but not required. Lesions in a previously irradiated area that have not progressed are not considered measurable.

You may not qualify if:

• Has received more than 2 lines of prior systemic therapy for locally advanced/metastatic breast cancer.
• Had prior exposure to any signal transducer and activator of transcription 3 (STAT3) inhibitor.
• Had radiotherapy within 3 weeks prior to Cycle 1 Day 1 (cycle is 28 days). Participants must have recovered from radiotherapy toxicities prior to starting study treatment and recovered to Grade 1 or better from related side effects of such therapy (with the exception of alopecia).
• Has HER2 overexpression by local laboratory testing (immunohistochemical \[IHC\] 3+ or in situ hybridization positive).
• Has known loss of retinoblastoma tumor suppressor gene (Rb) (testing not mandatory).
• Has had disease progression on more than two cyclin-dependent kinase (CDK)4/6 inhibitors. Adjuvant abemaciclib is allowed but must have progressed on palbociclib or ribociclib.
• Concurrently using other anticancer therapy. Participants must continue palbociclib and AI or fulvestrant for Phase 1b and palbociclib or ribociclib and AI or fulvestrant for Phase 2.

Sponsors & Collaborators

• Tvardi Therapeutics, Incorporated: lead
• National Cancer Institute (NCI): collaborator

Study Sites (6)

Holy Cross Health Fort Lauderdale - Holy Cross Hospital

Fort Lauderdale, Florida, 33308, United States

Location

Washington University School of Medicine Siteman Cancer Center

St Louis, Missouri, 63110, United States

Location

Vanderbilt - Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

Texas Oncology - Dallas Fort Worth (DFW) - Baylor Charles A. Sammons Cancer Center

Dallas, Texas, 75246, United States

Location

Harold C. Simmons Comprehensive Cancer Center

Dallas, Texas, 75390, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

C188-9 compound; palbociclib; Aromatase Inhibitors; Fulvestrant; ribociclib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones

Limitations and Caveats

Early termination lead to small numbers of subjects analyzed. For pharmacodynamic endpoints, pre- and on-treatment tissue biopsies were attempted to be obtained on all subjects, however due to tissue heterogeneity, only two subjects had paired biopsies and sufficient tissue available for analysis of pY-STAT1 and pY-STAT3. Baseline H-scores for pY-STAT1 fell below the biologically relevant score of 30 for both subjects, therefore, the pY-STAT1 outcome reported is not a reliable result.

Results Point of Contact

• Title: John Kauh, MD, Chief Medical Officer
• Organization: Tvardi Therapeutics

drugsafety@tvardi.com

713-489-8654

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: May 17, 2022
• First Posted: May 20, 2022
• Study Start: January 9, 2023
• Primary Completion: May 6, 2024
• Study Completion: May 6, 2024
• Last Updated: September 24, 2026
• Results First Posted: September 24, 2026

Record last verified: 2026-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)