ATI-450 in Combination With Paclitaxel or Capecitabine in Patients With Hormone Receptor-positive and HER2 Negative Metastatic Breast Cancer With Bone Metastasis

Breast Cancer Clinical Trial

Official title:

A Phase I/II Trial of ATI-450 in Combination With Paclitaxel or Capecitabine in Patients With Hormone Receptor-positive and HER2 Negative Metastatic Breast Cancer With Bone Metastasis

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04606342
• Other study ID #: 20-x343
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: December 31, 2020
• Est. completion date: April 30, 2028

Study information

• Verified date: October 2020
• Source: Washington University School of Medicine
• Contact: Cynthia X Ma, M.D., Ph.D.
• Phone: 314-362-8903
• Email: cynthiaxma[@]wustl.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a dose-escalating phase I using a rolling 6 design and randomized phase II study of ATI-450 in combination with chemotherapy testing the hypothesis that the combination of chemotherapy (paclitaxel or capecitabine) and ATI-450 will improve progression-free survival and reduce bone turnover, improve patient bone density, improve patient quality of life, and improve clinical efficacy.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 150
• Est. completion date: April 30, 2028
• Est. primary completion date: May 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Phase I: Biopsy-proven hormone receptor-positive, HER2 negative metastatic breast cancer with bone metastasis.
• Phase II: Biopsy-proven hormone receptor-positive, HER2 negative metastatic breast cancer with progressive bone metastasis per the latest tumor imaging studies.
• Measurable or non-measurable but evaluable disease by RECIST v 1.1.
• No more than one prior chemotherapy for metastatic disease (phase II only). There are no limits on prior endocrine therapy-based regimens.
• Phase I: Washout from prior chemotherapy other than capecitabine (for the capecitabine cohort) or paclitaxel (for the paclitaxel cohort) for 3 weeks or passed 5 half-lives and recovered AEs to grade 1 (except for alopecia).
• Phase II: Washout from prior chemotherapy for 3 weeks or passed 5 half-lives and recovered AEs to grade 1 (except for alopecia).
• A washout period of 1 week is required from the completion of radiation therapy.
• Phase I: Planning to start or on stable doses of capecitabine (for the capecitabine cohort: no less than 1000 mg/m2 BID, 14 days on and 7 days off) or paclitaxel (for the paclitaxel cohort: no less than 80 mg/m2 weekly dosing).
• Phase II: Candidate for initiating capecitabine or paclitaxel treatment per physician decision.
• At least 18 years of age.
• ECOG performance status = 2
• Life expectancy of at least 12 weeks.
• Adequate bone marrow and organ function as defined below:
• Leukocytes = 3,000/mcL
• Absolute neutrophil count = 1,500/mcL
• Platelets = 100,000/mcL
• Total bilirubin = 1.5 x IULN
• AST(SGOT)/ALT(SGPT) = 3.0 x IULN
• Creatinine clearance > 60 mL/min by Cockcroft-Gault
• Prior treatment with denosumab and zoledronic acid is allowed if at least 4 weeks have passed before the start of study treatment.
• The effects of ATI-450 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and 30 days after completion of the study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and 90 days after completion of the study
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• A history of other malignancy with the exception of malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease.
• Currently receiving any other investigational agents.
• Untreated brain metastases. Patients with treated brain metastases are eligible if they show no evidence of progression and are off steroids.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to ATI-450 or other agents used in the study.
• History of acute, untreated skeletal related events (SRE) or active untreated SRE or a change or an anticipated change in the SOC antiresorptive agents after entering the study (phase II only).
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
• Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Cancer of Breast

Intervention

Drug:
• ATI-450
Patients should take ATI-450 at approximately the same times every day, with or without food.
• Paclitaxel
-Given standard of care
• Capecitabine
-Given standard of care
• Antiresorptive Agents
-Either bisphosphonate or denosumab given per standard of care

Locations

Country	Name	City	State
United States	Kansas University	Kansas City	Kansas
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (3)

Lead Sponsor	Collaborator
Washington University School of Medicine	Aclaris Therapeutics, Inc., United States Department of Defense

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of toxicities as measured by CTCAE v. 5.0 (Phase I only)		From baseline through 30 days after end of treatment (estimated to be 11 months)
Primary	Progression-free survival (PFS) (Phase II only)	PFS is defined from date of treatment start to date of progression or date of death or date of last imaging showing progression free if no progression or death occurs.; Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).	Through disease progression or end of treatment (estimated to be 10 months)
Primary	Percent change in serum CTX at Week 13 relative to baseline (Phase II only)	-% reduction in sCTx at week 13 relative to baseline will be calculated as (week 13 sCTx /baseline sCTx -1) ×100%.	Baseline and week 13
Secondary	Changes in Inflammatory cytokines as measured by clinical laboratory assay (Phase I only)		Baseline, cycle 1 day 15, day 1 of each cycle (each cycle is 21 days long), and at progression (estimated to be 10 months)
Secondary	Immune markers as measured by patient's plasma (Phase I only)	-Patient's plasma will be analyzed for immune markers using the Luminex system	Baseline, day 1 of each cycle (each cycle is 21 days long), and at progression (estimated to be 10 months)
Secondary	Steady state ATI-450 trough concentration (Phase I only)	-ATI-450 concentrations in plasma samples are determined by LC-MS/MS following protein precipitation using a validated method	Cycle 2 Day 1 (approximately Day 22 - each cycle is 21 days long)
Secondary	Changes in bone turnover markers as measured by ELISA (Phase II only)		Baseline, cycle 1 day 8 (each cycle is 21 days long), and at progression (estimated to be 10 months)
Secondary	Changes in inflammatory cytokines as measured by clinical laboratory assay (Phase II only)		Baseline, cycle 1 day 15, day 1 of each cycle (each cycle is 21 days long), and at progression (estimated to be 10 months)
Secondary	Time to maximum reduction of serum CTX (Phase II only)		Baseline, cycle 1 day 1, cycle 1 day 8, cycle 1 day 15, day 1 of each cycle (each cycle is 21 days long), and at progression (estimated to be 10 months)
Secondary	Incidence of adverse events as measured by CTCAE v. 5.0 (Phase II only)		From baseline through 30 days after end of treatment (estimated to be 11 months)
Secondary	Change in quality of life as measured by EORTC QLQ-C30 (Phase II only)	-The QLQ-C30 is composed of five functional scales, three symptom scales, a global health status/QoL scale and six single items. All of the scales and single-item measures range in score from 0 to 100. A high score of functional scale, symptom scales and global health status/QoL scale corresponds to a high/healthy level of functioning, high level of symptomatology/problems, and high QoL, respectively	Prior to start of treatment, cycle 5 day 1 (each cycle is 21 days long), every 4 cycles thereafter, and at progression (estimated to be 10 months)
Secondary	Change in pain as measured by Brief Pain Inventory (Phase II only)	-Brief pain inventory (BPI) rapidly assesses the severity of pain and its impact on daily functioning. It assesses the severity of pain, impact of pain on daily function, location of pain, pain medications and amount of pain relief in the past 24 hours or the past week. This version has front and back body diagrams, the four pain severity items and seven pain interference items rated on 0-10 scales, and the question about percentage of pain relief by analgesics.	Prior to start of treatment, cycle 3 day 1 (each cycle is 21 days long), every 2 cycles thereafter, and at progression (estimated to be 10 months)
Secondary	Change in neuropathy as measured by CIPN20 (Phase II - paclitaxel containing arm only)	-Chemotherapy-induced peripheral neuropathy 20-item scale (CIPN20) provides sensory, motor, and autonomic subscales. It is a validated instrument designed to elicit cancer patients' experience of symptoms and functional limitations related to chemotherapy-induced peripheral neuropathy.	Prior to start of treatment, cycle 3 day 1 (each cycle is 21 days long), every 2 cycles thereafter, and at progression (estimated to be 10 months)
Secondary	Overall response rate (ORR) (Phase II only)	ORR: Number of complete response + partial response; Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).; Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.	Through completion of treatment (estimated to be 10 months)
Secondary	Clinical benefit rate (CBR) (Phase II only)	CBR is defined number of patients with complete response (CR) and partial response (PR); Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).; Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters	24 weeks
Secondary	Overall survival (OS) (Phase II only)		Through completion of follow-up (estimated to be 46 months)

External Links

•   Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine