Study of TTI-101 in Combination for Participants With Metastatic Hormone Receptor-Positive and Human Epithelial Receptor 2 (HER2)-Negative Breast Cancer

Sponsor

Tvardi Therapeutics, Incorporated (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05384119

Collaborator

(none)

Enrollment

Location

Arms

32.1

Anticipated Duration (Months)

1.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objectives of the Phase 1b part of this study are to evaluate the safety and tolerability of TTI-101 when added to palbociclib and aromatase inhibitor (AI) administered orally to participants with estrogen receptor-positive (ER+) human epithelial 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.

The primary objective of the Phase 2 part of this study is to evaluate tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria in participants who receive TTI-101 added to palbociclib and AI.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: TTI-101 Drug: Palbociclib Drug: Aromatase inhibitor (AI)	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

53 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase 1b/2 Study of the Addition of STAT3 Inhibitor TTI-101 to Reverse Resistance on First- Line Palbociclib Plus Aromatase Inhibitor Therapy for Metastatic Hormone Receptor-Positive and HER2-Negative Breast Cancer

Anticipated Study Start Date :

Jun 1, 2022

Anticipated Primary Completion Date :

Dec 1, 2024

Anticipated Study Completion Date :

Feb 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1b: Dose Escalation Participants will receive up to 3 dose levels of TTI-101 added to palbociclib and AI to determine the RP2D.	Drug: TTI-101 Oral tablet Drug: Palbociclib Oral capsule Other Names: Ibrance ® Drug: Aromatase inhibitor (AI) Oral tablet
Experimental: Phase 2: Dose Expansion 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 and AI.	Drug: TTI-101 Oral tablet Drug: Palbociclib Oral capsule Other Names: Ibrance ® Drug: Aromatase inhibitor (AI) Oral tablet

Arm

Intervention/Treatment

Experimental: Phase 1b: Dose Escalation

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

Drug: TTI-101

Oral tablet

Drug: Palbociclib

Oral capsule

Other Names:

Ibrance ®

Drug: Aromatase inhibitor (AI)

Oral tablet

Experimental: Phase 2: Dose Expansion

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 and AI.

Drug: TTI-101

Oral tablet

Drug: Palbociclib

Oral capsule

Other Names:

Ibrance ®

Drug: Aromatase inhibitor (AI)

Oral tablet

Outcome Measures

Primary Outcome Measures

Phase 1b: 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) [Up to approximately 18 months]
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 will be recorded as AEs.
Phase 1b: Number of Participants Who Experience a Serious Adverse Event (SAE) [Up to approximately 18 months]
Phase 2: Clinical Benefit Rate (CBR) [Up to approximately 18 months]
Defined as complete response (CR) + partial response (PR) + stable disease (SD) for at least 6 months.

Secondary Outcome Measures

Phase 1b: Clinical Benefit Rate (CBR) [Up to approximately 18 months]
Defined as complete response (CR) + partial response (PR) + stable disease (SD) for at least 6 months.
Phase 1b and Phase 2: Overall Response Rate (ORR) [Up to approximately 18 months]
Defined as complete response (CR) + partial response (PR) measured in all participants using RECIST Version 1.1.
Phase 1b and Phase 2: Overall Response Rate (ORR) [Up to approximately 18 months]
Defined as complete response (CR) + partial response (PR) measured using RECIST Version 1.1 in participants who have a follow-up on-study tumor assessment at least 42 days following Cycle 1 Day 1 (cycle is 28 days) and who receive at least 80% of scheduled dosing with TTI-101.
Phase 1b and Phase 2: Maximum Observed Plasma Concentration (Cmax) of TTI-101 [Cycle 1 Day 1 to Cycle 3 Day 1 (cycle is 28 days)]
Phase 1b and Phase 2: Time of Maximum Observed Plasma Concentration (Tmax) of TTI-101 [Cycle 1 Day 1 to Cycle 3 Day 1 (cycle is 28 days)]
Phase 1b and Phase 2: Area Under the Plasma Concentration-time Curve from Time 0 to Time t (AUC[0-t]) of TTI-101 [Cycle 1 Day 1 to Cycle 3 Day 1 (cycle is 28 days)]
Time t is defined as the time point for the last sample on the pharmacokinetic profile in which quantifiable drug is detected.
Phase 1b and Phase 2: Pharmacodynamics of TTI-101 as Measured By Change from Baseline in Percentage of Phosphorylated Signal Transducer and Activator of Transcription 1 (pY-STAT1) Positive Cells in Tumor Biopsy Samples [Baseline up to approximately 18 months]
Phase 1b and Phase 2: Pharmacodynamics of TTI-101 as Measured By Change from Baseline in Percentage of Phosphorylated Signal Transducer and Activator of Transcription 3 (pY-STAT3) Positive Cells in Tumor Biopsy Samples [Baseline up to approximately 18 months]
Phase 1b and Phase 2: Pharmacodynamics of TTI-101 as Measured By Change from Baseline in Percentage of Phosphorylated Signal Transducer and Activator of Transcription 5 (pY-STAT5) Positive Cells in Tumor Biopsy Samples [Baseline up to approximately 18 months]
Phase 1b and Phase 2: Duration of Response (DoR) to Treatment [Up to approximately 18 months]
Phase 1b and Phase 2: Time to Tumor Progression (TTP) [Up to approximately 18 months]
Phase 1b and Phase 2: Best Overall Response (BOR) [Up to approximately 18 months]
Phase 1b and Phase 2: Progression-free Survival (PFS) [Up to approximately 18 months]
Phase 1b and Phase 2: Progression-free Survival (PFS) at 6 Months [Up to approximately 6 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.
Currently receiving palbociclib and AI therapy in the metastatic setting with evidence of progressive disease. In addition:

Must have remained on palbociclib and AI 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 and AI.
Must be continuing on palbociclib at a dose of 125, 100, or 75 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 hormone receptor-positive (estrogen receptor-positive [ER+], human epithelial receptor 2-negative [HER2-]) breast cancer per local laboratory testing.
Only 1 prior line of systemic treatment (palbociclib and AI) in the locally advanced or metastatic setting is allowed; the participant must have shown evidence of progressive disease on palbociclib and AI 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 first-line palbociclib and AI.
The presence of measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 is required. Lesions in a previously irradiated area that have not progressed are not considered measurable.

Exclusion Criteria:

Participants meeting any of the following exclusion criteria will not be eligible:

Has received more than 1 line 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 human epithelial receptor 2 (HER2) overexpression by local laboratory testing (immunohistochemical [IHC] 3+ or in situ hybridization positive).
Has known loss of retinoblastoma tumor suppressor gene (Rb) or estrogen receptor 1 (ESR1) activating mutation (testing not mandatory).
Has had disease progression on more than one cyclin-dependent kinase (CDK)4/6 inhibitor or has progressed more than once on the same CDK4/6 inhibitor.
Concurrently using other anticancer therapy. Participants should continue palbociclib and AI therapy.