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

Tvardi Therapeutics

Status and phase: Terminated; Phase 1

Conditions: Breast Cancer

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

Study type: Interventional

Funder types: Industry

Identifiers

NCT05384119

TVD-101-002B

Details and patient eligibility

About

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.

Enrollment: 6 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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 exclusion criteria will not be eligible:

1. Has received more than 2 lines of prior systemic therapy for locally advanced/metastatic breast cancer.
2. Had prior exposure to any signal transducer and activator of transcription 3 (STAT3) inhibitor.
3. 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).
4. Has HER2 overexpression by local laboratory testing (immunohistochemical [IHC] 3+ or in situ hybridization positive).
5. Has known loss of retinoblastoma tumor suppressor gene (Rb) (testing not mandatory).
6. 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.
7. 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 design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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6 participants in 2 patient groups

Phase 1b: Dose Escalation

Experimental group

Description:

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

Treatment:

Drug: TTI-101

Drug: fulvestrant

Drug: Aromatase inhibitor (AI)

Drug: Palbociclib

Phase 2: Dose Expansion

Experimental group

Description:

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.

Treatment:

Drug: TTI-101

Drug: fulvestrant

Drug: Aromatase inhibitor (AI)

Drug: Palbociclib

Drug: ribociclib