ALX148 + Chemotherapy + Immunotherapy for Ovarian Cancer

Overseen By Lucia Borasso, BSN

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Haider Mahdi

Must not be taking: Immunosuppressants, Corticosteroids, PD1 inhibitors, others

Disqualifiers: Sarcoma, CNS metastases, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: 1

Duration: Up to 2 years

31 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug combination for ovarian cancer that has returned and resists common platinum-based treatments. It combines chemotherapy and immunotherapy with ALX148 (Evorpacept), which may enhance the immune system's ability to target cancer cells. Individuals with recurrent epithelial ovarian cancer who have tried several treatments without success might be suitable candidates. Participation can help researchers determine if this new combination effectively shrinks tumors or slows their growth. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that prior systemic anti-cancer therapy should not have been taken within 4 weeks before starting the trial, and certain immunosuppressive therapies are not allowed. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study found that using ALX148 with other treatments led to some serious side effects. Two patients died from rare immune system reactions linked to the trial drugs. However, other studies have shown that ALX148 can be safe with careful monitoring.

Doxorubicin, a common cancer treatment, is usually well-tolerated but can cause side effects like heart problems and low blood cell counts.

Pembrolizumab is also part of this trial. This immunotherapy drug treats various cancers and is generally considered safe, though some people might feel tired or have skin reactions.

This trial is in an early phase, so researchers are closely studying safety. While known risks exist, careful monitoring helps manage them. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ALX148 with pembrolizumab and doxorubicin for ovarian cancer because it offers a novel approach to treatment. Unlike standard therapies, which often rely on surgery, chemotherapy, or single-agent immunotherapy, this regimen combines a new agent, ALX148, with existing drugs for a potentially more powerful effect. ALX148 works by blocking the CD47 protein, often referred to as a "don't eat me" signal that cancer cells use to evade the immune system. By combining this with pembrolizumab, an immune checkpoint inhibitor, and doxorubicin, a chemotherapy agent, the treatment aims to enhance the immune system's ability to target and destroy cancer cells more effectively. This multi-faceted approach could lead to better outcomes for patients with ovarian cancer.

What evidence suggests that ALX148 combined with chemotherapy and immunotherapy could be effective for ovarian cancer?

In this trial, participants will receive a combination of ALX148, doxorubicin, and pembrolizumab, which research suggests might be effective against ovarian cancer. ALX148 aids the immune system by blocking a protein called CD47, which cancer cells use to evade detection. This combination could enhance the immune system's ability to locate and attack cancer cells. Specifically, studies have shown that a special form of doxorubicin, called pegylated liposomal doxorubicin, helped 26% of ovarian cancer patients who did not respond to other treatments. Adding pembrolizumab, a drug that boosts the immune system, might increase the treatment's effectiveness. Overall, this combination aims to improve outcomes for patients with ovarian cancer that has not responded to standard treatments. ^{1 4 5 6 7}

Who Is on the Research Team?

Alexander B. Olawaiye

Principal Investigator

UPMC Hillman Cancer Center

Are You a Good Fit for This Trial?

This trial is for women over 18 with recurrent epithelial ovarian cancer that's resistant to platinum-based therapy. They must have had fewer than six prior treatments, an ECOG performance status of 0-1, and measurable disease. Participants need normal organ/marrow function, known BRCA status, and agree to contraception if applicable.

Inclusion Criteria

I know my BRCA gene status or am willing to get tested.

There is a preserved tumor tissue sample from when you were first diagnosed, or from a later site if the cancer spread.

Willing to use highly effective contraception throughout the study and for at least 4 months after last treatment administration if childbearing potential exists.

Exclusion Criteria

I have a history of immune-related bowel or lung conditions.

I have brain metastases that need steroids for symptoms.

Patients who are pregnant or breast feeding or expecting to conceive or father children within the projected duration of the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Treatment

Participants receive Pegylated Liposomal Doxorubicin, pembrolizumab, and ALX148 every 21 days until disease progression or unacceptable toxicity

Up to 2 years

Maintenance Therapy

For patients with a complete response, maintenance therapy with pembrolizumab and ALX148 continues for 12 months

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-5 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• ALX148
• Doxorubicin
• Pembrolizumab

Trial Overview The trial tests ALX148 combined with liposomal doxorubicin and pembrolizumab in patients with ovarian cancer who've shown resistance to platinum therapies. It aims to enhance the effectiveness of immunotherapy by targeting CD47 on tumor cells.

How Is the Trial Designed?

Group I: ALX148 + Doxorubicin (PLD) + Pembrolizumab Experimental Treatment 3 Interventions

Given on Day 1 of each 21 day cycle, in the following order of administration: 200 mg IV pembrolizumab\* (maximum of 2 years (approximately 35 cycles) 45 mg/kg IV ALX148 30 mg/m\^2 IV doxorubicin (Pegylated Liposomal Doxorubicin (PLD)\* \*standard of care

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

Approved in United States as Adriamycin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in European Union as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Canada as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Japan as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Who Is Running the Clinical Trial?

Haider Mahdi

Lead Sponsor

Trials

6

Recruited

130+

Alexander B Olawaiye, MD

Lead Sponsor

Trials

4

Recruited

130+

ALX Oncology

Collaborator

Trials

1

Recruited

30+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

In a phase I trial involving 28 patients with advanced ovarian cancer, the combination of doxorubicin, paclitaxel, and cisplatin was found to be feasible and well tolerated, with a clinical response observed in 84% of evaluable patients.

The maximum tolerated dose was not established, but the recommended dose for further studies was determined to be 50 mg/m² of doxorubicin, as the treatment showed manageable toxicity and significant efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin, paclitaxel and escalating doses of doxorubicin (TAP) in advanced ovarian cancer: a phase I trial. Onda, T., Katsumata, N., Tsunematsu, R., et al.[2019]

Research is focusing on non-cross-resistant drugs like oxaliplatin and topotecan for treating drug-resistant ovarian cancer, with many being tested in combination therapies to improve outcomes.

Innovative strategies such as anticancer vaccines and gene therapy are being explored, highlighting the importance of clinical trials for women with advanced ovarian cancer due to low current cure rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Innovative therapies for advanced ovarian cancer. Trimble, EL.[2012]

In a phase II study involving 63 patients with ovarian cancer, pegylated liposomal doxorubicin (Doxil) showed a response rate of 19% in patients with measurable disease and a median overall survival of 10 months, indicating its efficacy in a heavily pretreated population.

Doxil was well tolerated, with manageable side effects; serious toxicities were relatively low, and nausea and vomiting were uncommon, suggesting a favorable safety profile compared to traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of liposomal doxorubicin in advanced gynecologic cancers. Israel, VP., Garcia, AA., Roman, L., et al.[2013]

Caelyx/Doxil, a pegylated liposomal formulation of doxorubicin, has a unique pharmacokinetic profile that allows it to effectively target tumor sites while reducing toxicity compared to traditional doxorubicin.

It has been approved by the FDA and EMEA for treating AIDS-related Kaposi's sarcoma and recurrent epithelial ovarian cancer, and is being investigated for use in various other cancers, indicating its potential as a versatile treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Caelyx/Doxil for the treatment of metastatic ovarian and breast cancer. Tejada-Berges, T., Granai, CO., Gordinier, M., et al.[2022]

A modified regimen of liposomal doxorubicin at 40 mg/m² every 4 weeks resulted in significantly less toxicity compared to the standard dose, with only 12% of patients experiencing grade 2 hand-foot syndrome and 8% experiencing stomatitis.

Despite the reduced toxicity, the treatment showed limited antineoplastic activity, with 9% of evaluable patients demonstrating an objective response in a group of 49 patients with platinum/paclitaxel-refractory ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 trial of liposomal doxorubicin (40 mg/m(2)) in platinum/paclitaxel-refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. Markman, M., Kennedy, A., Webster, K., et al.[2022]

This study analyzed over 7.5 million reports from the FDA Adverse Event Reporting System and found that conventional doxorubicin (DOX) has a higher incidence of adverse events compared to liposomal formulations, particularly in terms of myelosuppression and cardiotoxicity.

Liposomal DOX, especially the PEGylated version, showed lower reporting odds ratios for serious side effects like myelosuppression and cardiotoxicity, but a higher risk for palmar-plantar erythrodysesthesia (PPE), indicating the need for careful monitoring when using these formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. Fukuda, A., Tahara, K., Hane, Y., et al.[2022]

Paeonol (Pae) has been shown to protect against doxorubicin (Dox)-induced cardiotoxicity in both rat models and primary cardiomyocytes by enhancing mitochondrial fusion and restoring cardiac function.

The protective mechanism involves the PKCε-Stat3-Mfn2 signaling pathway, where Pae activates Stat3 to promote Mfn2-mediated mitochondrial fusion, without compromising the anticancer efficacy of Dox.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. Ding, M., Shi, R., Fu, F., et al.[2023]

Pegylated liposomal doxorubicin (Doxil/Caelyx) showed a 26% objective response rate in pretreated ovarian cancer patients, leading to further studies confirming its effectiveness.

In a phase III trial comparing Caelyx to topotecan, both drugs demonstrated equivalent response rates and survival outcomes, but they differed in toxicity profiles, suggesting Caelyx could be integrated into first-line treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III data on Caelyx in ovarian cancer. Muggia, F., Hamilton, A.[2019]

The combination of doxorubicin, carboplatin, and weekly paclitaxel in treating advanced epithelial ovarian cancer (EOC) shows activity, with 4 out of 12 patients achieving partial remission and 3 having stable disease.

The main toxicity observed was myelosuppression, particularly grade 4 neutropenia, but the weekly administration of paclitaxel allowed for maintaining an effective dose intensity (approximately 65 mg/m²/week) while managing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of carboplatin, doxorubicin and weekly paclitaxel in patients with advanced ovarian carcinoma. Hess, V., Verrill, MW., Bomphray, CC., et al.[2020]

Liposomal doxorubicin was effective in treating recurrent ovarian cancer, showing a 27% response rate, including complete and partial responses, even in patients with resistant tumors.

The treatment had manageable toxicity, with only mild hematological side effects and minimal severe reactions, indicating it is well tolerated even after multiple prior treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The clinical utility of liposomal doxorubicin in recurrent ovarian cancer. Campos, SM., Penson, RT., Mays, AR., et al.[2014]

Paclitaxel has been established as an effective treatment for newly diagnosed ovarian cancer patients, leading to its incorporation into primary chemotherapy regimens, particularly in combination with cisplatin as the new standard in the U.S.

Ongoing clinical trials are exploring various strategies to optimize paclitaxel-based chemotherapy, including comparisons of different platinum-based drugs and infusion schedules, as well as evaluating high-dose therapies with stem cell support.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy of advanced ovarian cancer: current status and future directions. Ozols, RF., Vermorken, JB.[2015]

In a study involving 829 patients with platinum-refractory or -resistant ovarian cancer, patupilone showed no significant improvement in overall survival compared to pegylated liposomal doxorubicin (PLD), with median survival rates of 13.2 months for patupilone and 12.7 months for PLD.

While patupilone had a higher overall response rate (15.5% vs. 7.9% for PLD), both treatments had similar disease control rates and common side effects, indicating that while patupilone may be more effective in achieving partial responses, it does not lead to longer survival compared to PLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, open-label, phase III study comparing patupilone (EPO906) with pegylated liposomal doxorubicin in platinum-refractory or -resistant patients with recurrent epithelial ovarian, primary fallopian tube, or primary peritoneal cancer. Colombo, N., Kutarska, E., Dimopoulos, M., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05467670

Safety and Efficacy of Anti-CD47, ALX148 in Combination ... Safety and Efficacy of Anti-CD47, ALX148 in Combination with Liposomal Doxorubicin and Pembrolizumab in Recurrent Platinum-resistant Ovarian Cancer.

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-03170

ALX148 in Combination with Liposomal Doxorubicin and ... Giving ALX148 in combination with PLD and pembrolizumab may kill more tumor cells in patients with recurrent platinum-resistant ovarian cancer. Eligibility ...

3. clin.larvol.com clin.larvol.com/trial-detail/NCT05467670

Safety and Efficacy of Anti-CD47, ALX148 in Combination ... Safety and Efficacy of Anti-CD47, ALX148 in Combination with Liposomal Doxorubicin and Pembrolizumab in Recurrent Platinum-resistant Ovarian Cancer. P2.

4. ir.alxoncology.com ir.alxoncology.com/news-releases/news-release-details/alx-oncology-announces-first-patient-dosed-phase-2-0

ALX Oncology Announces First Patient Dosed in Phase 2 ... We anticipate that the combination of evorpacept, liposomal doxorubicin and pembrolizumab may lead to improved efficacy and a more favorable ...

5. withpower.com withpower.com/trial/phase-2-ovarian-cancer-7-2022-63b78

ALX148 + Chemotherapy + Immunotherapy for Ovarian ... Research shows that pegylated liposomal doxorubicin (a form of doxorubicin) has shown a 26% response rate in ovarian cancer patients who did not respond to ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3530

Results of a phase 2 study of evorpacept (E, ALX148), ... There were two on-study deaths assessed as related to all three study drugs (hemophagocytic lymphohistiocytosis and cytokine release syndrome; 1 ...

7. alxoncology.com alxoncology.com/wp-content/uploads/2020/06/ALX-SITC-2018-Phase-1-Nov18.pdf

A Phase 1 Study of ALX148: CD47 Blockade in ... Patients experienced a best response of 1PR, 5SD (one SD >24weeks) with. 5 patients continuing on treatment. • HNSCC ALX148 + pembrolizumab: 4 evaluable ...