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A Phase Ib/II Study Confirmed Inhibition of Autophagy Synergizes Anti-tumor Effect of High Dose CDK4/6i

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ClinicalTrials.gov Identifier: NCT05953350
Recruitment Status : Recruiting
First Posted : July 20, 2023
Last Update Posted : December 13, 2023
Sponsor:
Information provided by (Responsible Party):
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Study Description
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Brief Summary:

In order to explore the safety and antitumor efficacy of different doses of CDK4/6 inhibitor Palbociclib in combination with the autophagy inhibitor hydroxychloroquine (HCQ) , a phase Ib/II study was conducted.

This study will adopt a 3+3 design and include three predefined dose groups of palbociclib: 100mg QD, 150mg QD, and 200mg QD. Initially, 600mg bid dose of hydroxychloroquine group will be administered in combination. The trial will use the first cycle (28 days) as the observation period for tolerability, observing and evaluating the occurrence of DLTs after medication and determining the maximum tolerated dose/maximum administered dose (MTD/MAD) and recommended phase 2 dose (RP2D) of the combination therapy.

This study improves the efficacy of CDK4/6 inhibitors in the treatment of solid tumors by reversing DTP status through the use of HCQ.


Condition or disease Intervention/treatment Phase
Inhibition of Autophagy Synergizes Anti-tumor Effect Drug: 600mg bid dose of hydroxychloroquine combined with three predefined dose groups of palbociclib Drug: RP2D dose of 600mg bid of hydroxychloroquine combined with palbociclib was selected for phase II clinical trial. Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 29 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib/II Study Confirmed Inhibition of Autophagy Synergizes Anti-tumor Effect of High Dose CDK4/6i With Manageable Safety in HR+HER2-breast Cancer Patients
Actual Study Start Date : June 12, 2023
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Phase Ib clinical trial
600mg bid dose of hydroxychloroquine group combined with three predefined dose groups of palbociclib: 100mg QD, 150mg QD, and 200mg QD, separately.
 Drug: 600mg bid dose of hydroxychloroquine combined with three predefined dose groups of palbociclib
hydroxychloroquine group of 600mg bid combined with three predefined dose groups of palbociclib: 100mg QD, 150mg QD, and 200mg QD, separately.
Experimental: Phase II clinical trial
After MTD was determined, RP2D dose was selected for phase II clinical trial.
 Drug: RP2D dose of 600mg bid of hydroxychloroquine combined with palbociclib was selected for phase II clinical trial.
After the exploration of 600mg bid dose of hydroxychloroquine combined with palbociclib, and the maximal tolerated dose (MTD) was determined, then RP2D dose of 600mg bid dose of hydroxychloroquine combined with palbociclib was selected for phase II clinical trial.


Outcome Measures
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Primary Outcome Measures :
  1. The safety dose of the combination of hydroxychloroquine and CDK4/6 inhibitors in patients [ Time Frame: 12 months ]

    The study aims to evaluate the safety dose of the combination of hydroxychloroquine and CDK4/6 inhibitors in patients with solid tumors. The safety dose was according to "3+3" dose escalation principle.

    In this study, Dose-limiting toxicity (DLT) was defined as drug-related adverse reactions (according to the NCI CTC 5.0 grading criteria) after treatment: ≥ Grade II liver and kidney injury, grade III other non-hematological toxicity, and grade IV hematological toxicity.


  2. the recommended phase II dose [ Time Frame: 12 months ]
    The study aims to evaluate the recommended phase II dose of the combination of hydroxychloroquine and CDK4/6 inhibitors in patients with solid tumors.


Secondary Outcome Measures :
  1. Objective response rate（ORR） [ Time Frame: 12 months ]
    This study investigates the preliminary efficacy of the combination of hydroxychloroquine and CDK4/6 inhibitors in the treatment of solid tumors.

  2. Progression-free survival (PFS) [ Time Frame: 12 months ]
    This study investigates the preliminary efficacy of the combination of hydroxychloroquine and CDK4/6 inhibitors in the treatment of solid tumors.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients diagnosed with advanced solid tumors (including breast cancer, undifferentiated liposarcoma, etc.) confirmed by histology and/or cytology, who have failed CDK4/6 inhibitor treatment or have experienced failure of neoadjuvant or adjuvant CDK4/6 inhibitor therapy for 12 months.
  2. At least one measurable target lesion according to RECIST 1.1.
  3. Age 18 years or older, any gender.
  4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
  5. Expected survival of at least 3 months.
  6. Within one week before enrollment, baseline blood tests should be essentially normal (no blood transfusions or hematopoietic growth factor treatment within 14 days): absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; hemoglobin ≥ 9 g/dL; platelet count (PLT) ≥ 75 × 10^9/L.
  7. Within one week before enrollment, baseline liver and kidney function tests should be essentially normal (normal values determined by each study center's laboratory): total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); serum glutamic-pyruvic transaminase (SGPT/ALT) ≤ 3 × ULN (≤ 5 × ULN for patients with liver metastases or liver cancer); serum glutamic-oxaloacetic transaminase (SGOT/AST) ≤ 3 × ULN (≤ 5 × ULN for patients with liver metastases); serum creatinine ≤ 1.5 × ULN or creatinine clearance (Ccr) ≥ 50 ml/min.
  8. Fertile patients (both males and females) must agree to use a reliable contraceptive method concurrently with their partners during the trial and for at least 3 months after the last dose of medication (hormonal or barrier methods, or abstinence). Pre-menopausal female patients must have a negative pregnancy test in blood or urine before enrollment.
  9. Pre-menopausal women should provide blood and urine samples to confirm a negative pregnancy status and commit to using contraception during the study period and for 6 months after the study. Male participants are required to commit to using contraception with their partners or female partners during the study period and for 6 months after the study.

Exclusion Criteria:

  1. Patients who have undergone major visceral surgery (excluding needle biopsies) or significant trauma within 4 weeks prior to the first administration of the study drug.
  2. Prior treatment with radiotherapy and two or more CDK4/6 inhibitors for advanced or metastatic disease.
  3. Failure to recover from adverse reactions of previous anti-tumor therapy to CTCAE 5.0 grade ≤ 1 (except for acceptable toxicities without safety risks, such as hair loss, and manageable immune-related adverse reactions). Additionally, symptomatic peripheral neuropathy of CTCAE 5.0 grade ≥ 2 resulting from the previous treatment regimen.
  4. Clinical symptoms of central nervous system metastases or leptomeningeal metastases, or other evidence indicating uncontrolled central nervous system metastases or leptomeningeal metastases deemed unsuitable for enrollment by the investigator.
  5. Pregnancy (positive pregnancy test) or lactation.
  6. Active infection requiring systemic antimicrobial therapy that is not under control at present (except for asymptomatic urinary tract infections). History of immune deficiency, including positive HIV antibody testing. History of active hepatitis B (except for controlled cases with antiviral therapy) and positive hepatitis C antibody.
  7. History of severe cardiovascular or cerebrovascular diseases, including but not limited to clinically significant cardiac rhythm or conduction abnormalities requiring clinical intervention, ventricular arrhythmias, second- or third-degree atrioventricular block; average QTcF > 470 ms based on three consecutive 12-lead electrocardiograms at rest; acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or higher cardiovascular events within 6 months before the first dose; uncontrolled hypertension.
  8. Patients with psychiatric disorders or poor compliance.
  9. Patients unsuitable for hydroxychloroquine use due to the presence of retinal vascular disease.
  10. Other systemic medical history or conditions deemed inappropriate for participation in the trial by the investigator.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05953350


Contacts
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Contact: Tao Qin, Phd +8613570396232 qint6@mail.sysu.edu.cn
Contact: Chang Gong, Phd

Locations
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China, Guangdong
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University Recruiting
Guangzhou, Guangdong, China, 510120
Contact: Gong Chang, doctor    02034070499    changgong282@163.com   
Sponsors and Collaborators
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
More Information
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Responsible Party: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
ClinicalTrials.gov Identifier: NCT05953350    
Other Study ID Numbers: SKSKY-2023-488-01
First Posted: July 20, 2023    Key Record Dates
Last Update Posted: December 13, 2023
Last Verified: December 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University:
inhibition of autophagy
CDK4/6i
hydroxychloroquine
HR+HER2-breast cancer
Additional relevant MeSH terms:
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Hydroxychloroquine
Palbociclib
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
 Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents
Antineoplastic Agents
Protein Kinase Inhibitors