Breast CancerPhase 1NCT05384119
Phase 1b/2 Study of TTI-101 in Combination for Patients With Metastatic Hormone Receptor-Positive and HER2-Negative Breast Cancer
A Phase 1 study testing TTI-101, Palbociclib and Aromatase inhibitor (AI) in people with Breast Cancer, run by Tvardi Therapeutics, Incorporated at 6 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Breast Cancer
- What is being tested?
- TTI-101, Palbociclib and Aromatase inhibitor (AI)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 6 sitesUnited States
- Study dates
- 9 Jan 2023to 6 May 2024
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- Participants meeting any of the following exclusion criteria will not be eligible:
- 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.
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
United States6 sites
Texas Oncology - Dallas Fort Worth (DFW) - Baylor Charles A. Sammons Cancer Center
Dallas, Texas, 75246
Harold C. Simmons Comprehensive Cancer Center
Dallas, Texas, 75390
Holy Cross Health Fort Lauderdale - Holy Cross Hospital
Fort Lauderdale, Florida, 33308
University of Texas MD Anderson Cancer Center
Houston, Texas, 77030
Vanderbilt - Ingram Cancer Center
Nashville, Tennessee, 37232
Washington University School of Medicine Siteman Cancer Center
St Louis, Missouri, 63110
About this study
Official title: REVERT- Breast Cancer: Phase 1b/2 Study of the Addition of STAT3 Inhibitor TTI-101 to Reverse Resistance to Palbociclib or Ribociclib Plus Aromatase Inhibitor or Fulvestrant Therapy for Metastatic Hormone Receptor-Positive and HER2-Negative Breast Cancer
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
- Being tested
- TTI-101, Palbociclib, Aromatase inhibitor (AI), fulvestrant, ribociclib
- Keywords
- Breast cancer, HR+ HER2-, palbociclib-resistant breast cancer, TTI-101, STAT3 Inhibitor, Palbociclib, Aromatase inhibitor, ribociclib, fulvestrant
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TTI-101Drug
Oral tablet
PalbociclibDrug
Also called Ibrance ®
Oral capsule
Aromatase inhibitor (AI)Drug
Oral tablet
fulvestrantDrug
Oral tablet
ribociclibDrug
Oral tablet
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: TTI-101; Drug: Palbociclib; Drug: Aromatase inhibitor (AI); Drug: fulvestrant; Drug: ribociclib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phase 1b: Number of Participants Who Experience a Dose Limiting Toxicity (DLT)
Number of Participants Who Experience a Dose Limiting Toxicity (DLT)
Measured: 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.
Measured: 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)
Measured: Up to approximately 17 months
Phase 2: Landmark Progression Free Survival at 6 Months (PFS6)
Landmark Progression Free Survival at 6 Months (PFS6)
Measured: 6 months
Secondary outcomes (14)
Phase 1b: PFS6
Progression-free survival at 6-months.
Measured: 6 months
Phase 1b and Phase 2: Clinical Benefit Rate (CBR)
Defined as complete response (CR) + partial response (PR) + stable disease (SD) for at least 6 months at the recommended phase 2 dose (RP2D).
Measured: Up to approximately 17 months
Phase 1b and Phase 2: Overall Response Rate (ORR)
Defined as complete response (CR) + partial response (PR) measured in all participants using RECIST Version 1.1 at the recommended phase 2 dose (RP2D).
Measured: Up to approximately 17 months
Phase 1b and Phase 2: Overall Response Rate (ORR)
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.
Measured: Up to approximately 17 months
Phase 1b and Phase 2: Maximum Observed Plasma Concentration (Cmax) of TTI-101
Measured: Cycle 2 Day 1 (cycle is 28 days)
Phase 1b and Phase 2: Time of Maximum Observed Plasma Concentration (Tmax) of TTI-101
Measured: Cycle 2 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
AUC0_8 (h*ng/mL)
Measured: Cycle 2 Day 1 (cycle is 28 days)
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
Change in H-score=(1×%cells with 1+ intensity)+(2×%cells with 2+ intensity)+(3×%cells with 3+ intensity); the percentages are based on how many tumor cells fall into each intensity category; possible range: 0 to 300; baseline levels below 30 are considered not biologically relevant
Measured: Baseline to Cycle 3 Day 1 (cycle is 28 days)
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
Change in H-score=(1×%cells with 1+ intensity)+(2×%cells with 2+ intensity)+(3×%cells with 3+ intensity); the percentages are based on how many tumor cells fall into each intensity category; possible range: 0 to 300; baseline levels below 30 are considered not biologically relevant.
Measured: Baseline to Cycle 3 Day 1 (cycle is 28 days)
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
Change in H-score=(1×%cells with 1+ intensity)+(2×%cells with 2+ intensity)+(3×%cells with 3+ intensity); the percentages are based on how many tumor cells fall into each intensity category; possible range: 0 to 300; baseline levels below 30 are considered not biologically relevant
Measured: Baseline to Cycle 3 Day 1 (cycle is 28 days)
Phase 1b and Phase 2: Duration of Response (DoR) to Treatment
The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or PD is objectively documented (taking as reference for PD the smallest measurements recorded since the treatment started).
Measured: Up to approximately 17 months
Phase 1b and Phase 2: Time to Tumor Progression (TTP)
For Phase 1b Progression-free Survival (PFS) was calculated, defined as the duration of time from start of treatment to time of progression or death, whichever occurred first. TTP and PFS are equivalent in the Phase 1b cohort.
Measured: Up to approximately 17 months
Phase 1b and Phase 2: Best Overall Response (BOR)
BOR evaluated for patients at the recommended phase 2 dose (RP2D).
Measured: Up to approximately 17 months
Phase 2: Progression-free Survival (PFS)
Progression-free Survival (PFS) at the recommended phase 2 dose (RP2D).
Measured: Up to approximately 17 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 May 2022
- Study start9 Jan 2023
- Primary completion6 May 2024
- Study completion6 May 2024
Why it stopped: The study was terminated prior to Phase 2 due to slow accrual.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Tvardi Therapeutics, Incorporated
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05384119
- Sponsor's protocol ID
- TVD-101-002B
- Other IDs
- 5R01CA255960
- Status last verified
- Aug 2026
- First submitted
- 17 May 2022
- Last updated
- 24 Sep 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No