Breast Cancer
Conditions
Keywords
Breast cancer, HR+ HER2-, palbociclib-resistant breast cancer, TTI-101, STAT3 Inhibitor, Palbociclib, Aromatase inhibitor, ribociclib, fulvestrant
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.
Interventions
DRUGTTI-101
Oral tablet
DRUGPalbociclib
Oral capsule
Oral tablet
DRUGfulvestrant
Oral tablet
DRUGribociclib
Oral tablet
Sponsors
Tvardi Therapeutics, Incorporated
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants must meet all the following criteria to be eligible: 1. Age ≥18 years at the time of informed consent. 2. Metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy. 3. 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. 4. 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. 5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Has documented confirmation of histological or cytological HR-positive, HER2-negative breast cancer per local laboratory testing. 7. 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. 8. 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. 9. 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.
Exclusion criteria
Participants meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants Who Experience a Dose Limiting Toxicity (DLT) | Day 1 to Day 28 | Number of Participants Who Experience a Dose Limiting Toxicity (DLT) |
| Phase 1b: Number of Participants Who Experience an Adverse Event (AE) | Up to approximately 17 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 were recorded as AEs. |
| Phase 1b: Number of Participants Who Experience a Serious Adverse Event (SAE) | Up to approximately 17 months | Number of Participants Who Experience a Serious Adverse Event (SAE) |
| Phase 2: Landmark Progression Free Survival at 6 Months (PFS6) | 6 months | Landmark Progression Free Survival at 6 Months (PFS6) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: PFS6 | 6 months | Progression-free survival at 6-months. |
| Phase 1b and Phase 2: Clinical Benefit Rate (CBR) | Up to approximately 17 months | Defined as complete response (CR) + partial response (PR) + stable disease (SD) for at least 6 months at the recommended phase 2 dose (RP2D). |
| Phase 1b and Phase 2: Overall Response Rate (ORR) | Up to approximately 17 months | Defined as complete response (CR) + partial response (PR) measured in all participants using RECIST Version 1.1 at the recommended phase 2 dose (RP2D). |
| Phase 1b and Phase 2: Maximum Observed Plasma Concentration (Cmax) of TTI-101 | Cycle 2 Day 1 (cycle is 28 days) | — |
| Phase 1b and Phase 2: Time of Maximum Observed Plasma Concentration (Tmax) of TTI-101 | 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 | Cycle 2 Day 1 (cycle is 28 days) | AUC0\_8 (h\*ng/mL) |
| 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 to Cycle 3 Day 1 (cycle is 28 days) | 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 |
| 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 to Cycle 3 Day 1 (cycle is 28 days) | 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. |
| 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 to Cycle 3 Day 1 (cycle is 28 days) | 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 |
| Phase 1b and Phase 2: Duration of Response (DoR) to Treatment | Up to approximately 17 months | 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). |
| Phase 1b and Phase 2: Time to Tumor Progression (TTP) | Up to approximately 17 months | 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. |
| Phase 1b and Phase 2: Best Overall Response (BOR) | Up to approximately 17 months | BOR evaluated for patients at the recommended phase 2 dose (RP2D). |
| Phase 2: Progression-free Survival (PFS) | Up to approximately 17 months | Progression-free Survival (PFS) at the recommended phase 2 dose (RP2D). |
Countries
United States
Participant flow
Recruitment details
January 2023-May 2024. Recruitment was performed at three centers.
Pre-assignment details
6 patients were enrolled in the Phase 1b.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 |
Outcome results
None listed