Avelumab + Palbociclib/Hydroxychloroquine for Breast Cancer

(PALAVY Trial)

Recruiting at 7 trial locations

Overseen By Pauleen Sanchez, BA

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Abramson Cancer Center of the University of Pennsylvania

Must be taking: Adjuvant endocrine therapy

Must not be taking: Chronic high-dose corticosteroids

Disqualifiers: Chronic autoimmune, Cardiovascular, Diabetes, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 1

Duration: 24 weeks

96 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you must be on adjuvant endocrine therapy and cannot use tamoxifen if you are in the hydroxychloroquine group. If you are on tamoxifen, you may need to switch to an aromatase inhibitor at least 21 days before starting the trial. You can continue bone-modifying agents if you are already taking them.

What data supports the effectiveness of the drug combination Avelumab, Palbociclib, and Hydroxychloroquine for breast cancer?

Avelumab, a PD-L1 inhibitor, has shown antitumor activity in metastatic breast cancer, and Palbociclib has improved progression-free survival in advanced breast cancer when combined with other treatments. These findings suggest potential effectiveness when these drugs are used together for breast cancer. ^{1 2 3 4 5}

Is the combination of Avelumab, Palbociclib, and Hydroxychloroquine safe for humans?

Avelumab has been studied for safety in various cancers, including breast cancer, and is generally considered safe, but it can have side effects like hepatitis (liver inflammation), nephritis (kidney inflammation), and dermatitis (skin inflammation). Palbociclib and Hydroxychloroquine are also used in cancer treatments and have known safety profiles, but combining them with Avelumab may have unique risks that should be discussed with a healthcare provider. ^{1 2 6 7 8}

What makes the drug combination of Avelumab and Palbociclib/Hydroxychloroquine unique for breast cancer treatment?

This treatment is unique because it combines Avelumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with Palbociclib, a drug that stops cancer cells from dividing, and Hydroxychloroquine, which may enhance the effectiveness of cancer treatments. This combination targets cancer in multiple ways, which is different from standard treatments that usually focus on one mechanism. ^{4 9 10 11 12}

What is the purpose of this trial?

This clinical trial will assess the safety and early efficacy of Hydroxychloroquine or Avelumab, with or without Palbociclib, in early-stage ER+ breast cancer patients who are found to harbor disseminated tumor cells (DTCs) in the bone marrow after definitive surgery and standard adjuvant therapy.

Research Team

Angela DeMichele, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

This trial is for adults over 18 with early-stage ER+ breast cancer, who've completed primary and adjuvant therapy (except endocrine therapy), have no recurrent disease, and DTCs detected in bone marrow. They must not have had another invasive breast cancer or severe medical conditions like uncontrolled heart disease, lung dysfunction, or liver disease.

Inclusion Criteria

I don't have any health conditions that would prevent me from taking the study drugs.

I have finished all initial cancer treatments and any side effects are mild, except for hair loss or nerve issues.

I had stage II-III breast cancer that was ER+ and Her2-, treated with the goal of cure, and currently show no signs of the cancer returning.

Exclusion Criteria

Your EKG shows that your QT interval is longer than 480 milliseconds.

I am on high doses of steroids or other immune-weakening medicines.

I do not have any severe autoimmune diseases.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Avelumab, Hydroxychloroquine, and/or Palbociclib in various combinations over 6 cycles of 28 days each

24 weeks

Visits on Day 1 and Day 15 of each cycle for Avelumab administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term follow-up

Recurrence free survival (RFS) will be assessed 3 years after the completion of study treatment

3 years

Treatment Details

Interventions

• Avelumab
• HCQ
• Palbociclib

Trial Overview The trial tests the safety and efficacy of Hydroxychloroquine (HCQ) or Avelumab with/without Palbociclib on patients with dormant breast cancer cells post-surgery. It aims to see if these treatments can eliminate disseminated tumor cells in the bone marrow.

Participant Groups

Group I: Palbociclib and HCQ Experimental Treatment 2 Interventions

Patients will receive Palbociclib 75 mg daily, by mouth on D1-28 concurrently with HCQ, 600 mg twice daily D1-28 of each 28-day cycle.

Group II: Palbociclib and Avelumab Experimental Treatment 2 Interventions

Patients will receive Palbociclib 125 mg daily, by mouth on D1-21 concurrently with Avelumab, 10 mg/kg IV on D1 and D15 of each 28-day cycle

Group III: HCQ Experimental Treatment 1 Intervention

Patients will receive HCQ, 600 mg twice daily D1-28 of each 28-day cycle.

Group IV: Avelumab Experimental Treatment 1 Intervention

Patients will receive Avelumab, 10 mg/kg, IV, D1 and D15 of each 28-day cycle.

Avelumab is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in United States as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in Japan as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Who Is Running the Clinical Trial?

Abramson Cancer Center of the University of Pennsylvania

Lead Sponsor

Trials

360

Recruited

108,000+

Abramson Cancer Center at Penn Medicine

Lead Sponsor

Trials

425

Recruited

464,000+

Johns Hopkins University

Collaborator

Trials

2,366

Recruited

15,160,000+

Translational Breast Cancer Research Consortium

Collaborator

Trials

27

Recruited

3,100+

Breast Cancer Research Foundation

Collaborator

Trials

79

Recruited

40,500+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Findings from Research

In a phase 1 trial involving 168 patients with metastatic breast cancer (MBC), avelumab, a PD-L1 inhibitor, demonstrated an overall objective response rate of 3.0%, with a higher response rate of 5.2% in patients with triple-negative breast cancer (TNBC).

The study found that patients with PD-L1 positive tumor-associated immune cells had a significantly higher response rate to avelumab (16.7%) compared to those with PD-L1 negative cells (1.6%), suggesting that PD-L1 expression may help predict treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Dirix, LY., Takacs, I., Jerusalem, G., et al.[2022]

The JAVELIN Ovarian 200 trial is the first Phase III study to investigate the effectiveness of avelumab, a PD-L1 checkpoint inhibitor, in treating women with platinum-resistant ovarian cancer, involving multiple treatment arms to assess its efficacy.

The trial will measure overall survival and progression-free survival as primary outcomes, providing valuable insights into the potential benefits of avelumab alone or in combination with doxorubicin compared to doxorubicin alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design. Pujade-Lauraine, E., Fujiwara, K., Dychter, SS., et al.[2022]

The combination of durvalumab (a PD-L1 inhibitor) and olaparib (a PARP inhibitor) with standard paclitaxel chemotherapy significantly increased pathologic complete response (pCR) rates in stage II/III HER2-negative breast cancer, with rates rising from 20% to 37% overall.

While DOP showed enhanced efficacy, particularly in high-risk hormone receptor-positive/HER2-negative patients (pCR 64% vs. 22%), it also resulted in a higher incidence of immune-related grade 3 adverse events (12.3% vs. 1.3% in the control group).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial. Pusztai, L., Yau, C., Wolf, DM., et al.[2023]

In the FLIPPER trial, the combination of palbociclib and fulvestrant significantly improved progression-free survival (PFS) in postmenopausal women with HR+/HER2- advanced breast cancer compared to placebo and fulvestrant.

Patient-reported outcomes indicated that while global health status and quality of life (QoL) were maintained during treatment with palbociclib/fulvestrant, the time to deterioration in QoL was longer with placebo/fulvestrant, suggesting that palbociclib/fulvestrant is a beneficial treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial. Tibau, A., Martínez, MT., Ramos, M., et al.[2023]

The combination of tucatinib, letrozole, and palbociclib in a phase Ib/II trial for patients with HR+/HER2+ metastatic breast cancer showed a manageable safety profile, indicating it is a safe treatment option.

This all-oral, chemotherapy-free regimen demonstrated encouraging efficacy, suggesting it could serve as a potential maintenance or primary therapy for select patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can We De-escalate Therapy for HER2-Positive Metastatic Breast Cancer? Huppert, LA., Rugo, HS.[2023]

A 67-year-old male with lung squamous cell carcinoma developed myocarditis after receiving durvalumab, a PD-L1 inhibitor, highlighting the potential for serious cardiac side effects from this treatment.

The patient's myocarditis led to a significant decrease in heart function but improved rapidly with glucocorticoid therapy, suggesting that timely intervention can effectively manage this rare but severe adverse event.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case Report: Acute Myocarditis Due to PD-L1 Inhibitor Durvalumab Monotherapy in a Patient With Lung Squamous Cell Carcinoma. Zhou, B., Li, M., Chen, T., et al.[2022]

Avelumab is an antibody that blocks programmed cell death ligand-1 (PD-L1) and has received accelerated approval in the USA for treating metastatic Merkel cell carcinoma (mMCC) in both adults and children aged 12 and older.

The drug is also undergoing regulatory reviews for other cancer treatments, including urothelial carcinoma, indicating its potential as a versatile cancer therapy in various stages of development worldwide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab: First Global Approval. Kim, ES.[2022]

In a phase 1/2 trial involving 40 patients with recurrent gynecologic cancers, the combination of avelumab and utomilumab was found to be safe, with no serious immune-related adverse events reported.

The objective response rate (ORR) was low at 2.9% overall, but patients with cervical cancer showed a promising ORR of 11% and a disease control rate (DCR) of 78%, suggesting potential for further investigation in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1/2 trial of avelumab combined with utomilumab (4-1BB agonist), PF-04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies. Knisely, A., Ahmed, J., Stephen, B., et al.[2023]

In an expanded access trial involving 130 postmenopausal women with hormone receptor-positive (HR+)/HER2-negative advanced breast cancer, the combination of palbociclib and letrozole demonstrated a manageable safety profile, with the most common side effects being neutropenia (70%) and leukopenia (34.6%).

The objective response rate (ORR) was 24.8%, indicating that nearly a quarter of patients experienced a positive response to the treatment, with a median treatment duration of 10.6 months, suggesting a potential benefit for this patient population in Latin America.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expanded Access Study of Palbociclib Plus Letrozole for Postmenopausal Women with HR+/HER2- Advanced Breast Cancer in Latin America for Whom Letrozole Therapy is Deemed Appropriate. Fein, L., Lazaretti, N., Chuken, YL., et al.[2023]

Palbociclib is the first CDK 4/6 inhibitor approved for clinical use, specifically targeting advanced hormone receptor-positive breast cancer, which highlights its innovative role in cancer treatment.

The article reviews results from two significant clinical trials, emphasizing palbociclib's efficacy and its potential impact on managing HR-positive advanced breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib: First CDK4/6 Inhibitor in Clinical Practice for the Treatment of Advanced HR-Positive Breast Cancer. Ettl, J.[2020]

Palbociclib, a CDK4/6 inhibitor, significantly improves progression-free survival (PFS) in patients with hormone receptor-positive, Her2-negative advanced breast cancer, showing a median PFS of 20.2 months when combined with letrozole compared to 10.2 months with letrozole alone.

In previously treated patients, palbociclib combined with fulvestrant resulted in a median PFS of 9.2 months, compared to just 3.8 months with placebo, highlighting its efficacy in both first-line and subsequent treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib: A Novel Cyclin-Dependent Kinase Inhibitor for Hormone Receptor-Positive Advanced Breast Cancer. Mangini, NS., Wesolowski, R., Ramaswamy, B., et al.[2020]

In a study involving 82 postmenopausal women with heavily pretreated, endocrine therapy-resistant metastatic breast cancer, palbociclib combined with endocrine therapy demonstrated a clinical benefit rate of 41.5%, indicating significant efficacy in this challenging patient population.

The treatment was generally well-tolerated, with a favorable safety profile, although 43.9% of patients required dose adjustments or treatment delays, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palbociclib in highly pretreated metastatic ER-positive HER2-negative breast cancer. Hoste, G., Punie, K., Wildiers, H., et al.[2019]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Can We De-escalate Therapy for HER2-Positive Metastatic Breast Cancer? [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Case Report: Acute Myocarditis Due to PD-L1 Inhibitor Durvalumab Monotherapy in a Patient With Lung Squamous Cell Carcinoma. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Avelumab: First Global Approval. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Phase 1/2 trial of avelumab combined with utomilumab (4-1BB agonist), PF-04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies. [2023]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Expanded Access Study of Palbociclib Plus Letrozole for Postmenopausal Women with HR+/HER2- Advanced Breast Cancer in Latin America for Whom Letrozole Therapy is Deemed Appropriate. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Palbociclib: First CDK4/6 Inhibitor in Clinical Practice for the Treatment of Advanced HR-Positive Breast Cancer. [2020]

11. United States pubmed.ncbi.nlm.nih.gov

Palbociclib: A Novel Cyclin-Dependent Kinase Inhibitor for Hormone Receptor-Positive Advanced Breast Cancer. [2020]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Palbociclib in highly pretreated metastatic ER-positive HER2-negative breast cancer. [2019]