XTX101 + Atezolizumab for Solid Cancers

Recruiting at 16 trial locations

Overseen By Xilio Medical Affairs

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Xilio Development, Inc.

Must not be taking: Corticosteroids, Immunosuppressive drugs

Disqualifiers: Immunodeficiency, Active autoimmune, Active infection, others

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

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

Compensation: Varies

Number of Visits: Unknown

136 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a first-in-human, Phase 1/2, multicenter, open-label study designed to evaluate the safety and tolerability of vilastobart (XTX101) as monotherapy and vilastobart (XTX101) and atezolizumab combination therapy in patients with advanced solid tumors.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not have had any systemic anticancer therapy within 4 weeks or radiotherapy within 2 weeks before starting the study treatment.

What data supports the effectiveness of the drug XTX101 + Atezolizumab for solid cancers?

Pembrolizumab, a component of the treatment, has shown effectiveness in improving survival rates and response in various cancers, such as non-small cell lung cancer and melanoma, by helping the immune system attack cancer cells. ^{1 2 3 4 5}

Is the combination of XTX101 and Atezolizumab generally safe for humans?

Pembrolizumab (also known as Keytruda, MK-3475) has been used in various cancer treatments and is generally considered less toxic than traditional chemotherapy. However, it can cause side effects like pneumonitis (lung inflammation), fatigue, and nausea, among others. These side effects are important to consider when evaluating the safety of similar treatments. ^{1 2 6 7 8}

What makes the drug XTX101 + Atezolizumab unique for treating solid cancers?

XTX101 combined with Atezolizumab is unique because it involves a novel combination of immunotherapy agents, where XTX101 (also known as Pembrolizumab or KEYTRUDA) is a checkpoint inhibitor that helps the immune system recognize and attack cancer cells, while Atezolizumab is another checkpoint inhibitor targeting a different pathway, potentially enhancing the overall immune response against solid tumors. ^{9 10 11 12 13}

Eligibility Criteria

This trial is for adults with advanced solid tumors that have failed standard therapy or where no curative treatment exists. It's also open to those with metastatic melanoma who haven't had anti-PD-1/L-1 therapy, and people whose cancer progressed after such treatments. Participants must be in good physical condition (ECOG 0 or 1) and have proper organ function.

Inclusion Criteria

I have advanced small cell lung cancer and have undergone at least one treatment.

Patients with measurable disease per iRECIST (Part 1B and Part 1C only)

My cancer has worsened despite prior anti-PD-1 or anti-PD-L1 therapy.

Exclusion Criteria

I haven't had an infection needing IV drugs in the last 4 weeks or oral drugs in the last 2 weeks.

I have an autoimmune disease treated with strong medication in the last 2 years.

I have previously been treated with anti-CTLA-4 therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Part 1A - Dose Escalation

Vilastobart (XTX101) monotherapy administered in ascending doses to find the recommended phase 2 dose (RP2D)

8-12 weeks

Part 1B - Pharmacodynamic Dose Expansion

Vilastobart (XTX101) administered at the RP2D to examine pharmacodynamic biomarkers

8-12 weeks

Part 1C - Combination Dose Escalation

Vilastobart (XTX101) in combination with atezolizumab in a dose escalation/de-escalation design

8-12 weeks

Phase 2 - Dose Expansion

Vilastobart (XTX101) in combination with atezolizumab at the RP2D in patients with MSS CRC

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• Pembrolizumab
• XTX101

Trial Overview The study is testing XTX101 alone and combined with Atezolizumab in patients with various advanced solid tumors. It's a first-in-human study, meaning it's the first time these drugs are being tested in people, to see how safe they are and how well they're tolerated when given together or separately.

Participant Groups

Group I: Phase 2 - vilastobart (XTX101) Dose Expansion in Combination with Atezolizumab Experimental Treatment 2 Interventions

Phase 2 will receive a labeled dose of atezolizumab in combination with vilastobart (XTX101) at the RP2D(s) in patients with MSS CRC.

Group II: Part 1C - vilastobart (XTX101) Dose Escalation in Combination with Atezolizumab Experimental Treatment 2 Interventions

Part 1C will receive a labeled dose of atezolizumab in combination with vilastobart (XTX101).

Group III: Part 1B - Pharmacodynamic (PD) Dose Expansion Experimental Treatment 1 Intervention

Part 1B vilastobart (XTX101) at the RP2D will be administered to further examine vilastobart (XTX101) as monotherapy in patients with select advanced solid tumors.

Group IV: Part 1A - vilastobart (XTX101) Monotherapy Dose Escalation Experimental Treatment 1 Intervention

Part 1A Dose Escalation of vilastobart (XTX101) administered in ascending doses to patients with advanced or metastatic solid tumors to find the recommended phase 2 dose (RP2D).

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Xilio Development, Inc.

Lead Sponsor

Trials

3

Recruited

680+

Hoffmann-La Roche

Industry Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

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

Findings from Research

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Pembrolizumab (Keytruda) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

In the KEYNOTE-407 study, pembrolizumab combined with chemotherapy significantly improved overall survival (17.1 months) and progression-free survival (8.0 months) compared to placebo plus chemotherapy in patients with untreated metastatic squamous non-small cell lung cancer (NSCLC).

The study also found that patients receiving pembrolizumab plus chemotherapy had a longer time before disease progression on subsequent treatments (PFS-2), supporting its use as a standard first-line therapy, despite a similar rate of serious adverse events (grade 3 to 5) between the two treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407. Paz-Ares, L., Vicente, D., Tafreshi, A., et al.[2021]

In a long-term study of 123 patients with advanced nonsquamous NSCLC, the combination of pembrolizumab with pemetrexed-carboplatin significantly improved the objective response rate (58% vs. 33%) and progression-free survival (24.5 months vs. 9.9 months) compared to chemotherapy alone.

Patients who completed 2 years of pembrolizumab treatment had a remarkable 92% survival rate at the data cutoff, indicating a durable clinical benefit, while the safety profile remained manageable with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC. Awad, MM., Gadgeel, SM., Borghaei, H., et al.[2021]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Pembrolizumab (Keytruda) has been approved by the FDA for treating high-risk, non-muscle invasive bladder cancer (NMIBC) in patients who are unresponsive to BCG therapy and are either ineligible for or have opted not to undergo cystectomy.

This approval specifically targets patients with carcinoma in situ (CIS) with or without papillary tumors, highlighting its role as a treatment option for those with limited surgical options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approves Pembrolizumab for BCG-Unresponsive NMIBC. Wright, KM.[2021]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

In a phase II trial involving 221 men with metastatic castration-resistant prostate cancer, the combination of AT-101 with docetaxel and prednisone did not significantly improve overall survival compared to the placebo group, with median survival times of 18.1 months versus 17.8 months.

While AT-101 was generally well-tolerated, it did show some increased rates of serious side effects, such as cardiac events and pulmonary embolism, compared to the placebo, although a subgroup of high-risk patients did show a potential survival benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer. Sonpavde, G., Matveev, V., Burke, JM., et al.[2020]

In a phase I trial involving 30 patients with advanced taxane-pretreated ovarian and breast cancer, the combination of ixabepilone and pegylated liposomal doxorubicin (PLD) was found to be safe, with a recommended dose of 16 mg/m² of ixabepilone and 30 mg/m² of PLD.

The treatment showed objective responses in 23% of breast cancer patients and 29% of ovarian cancer patients, indicating potential efficacy and warranting further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of ixabepilone plus pegylated liposomal doxorubicin in patients with adenocarcinoma of breast or ovary. Chuang, E., Wiener, N., Christos, P., et al.[2021]

In a study using xenografts from human prostate cancer cell lines in mice, 636 genes were found to be differentially expressed in mitoxantrone-resistant prostate cancer, indicating significant genetic changes associated with treatment resistance.

The identified genes are linked to key processes such as androgen synthesis and drug efflux, suggesting potential targets for improving treatment effectiveness in advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of key genes and specific pathways potentially involved in androgen-independent, mitoxantrone-resistant prostate cancer. Zhu, S., Jiang, L., Wang, L., et al.[2022]

In a study involving 106 patients with metastatic breast cancer resistant to anthracyclines and taxanes, the combination of ixabepilone and capecitabine showed a 30% objective response rate, indicating its efficacy in this challenging patient population.

The maximum tolerated dose was established at 40 mg/m2 of ixabepilone with 2000 mg/m2 of capecitabine, and while there were some grade 3/4 side effects, the overall safety profile was considered acceptable, leading to ixabepilone's approval for use in resistant metastatic breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II study of ixabepilone plus capecitabine in anthracycline-pretreated/resistant and taxane-resistant metastatic breast cancer. Bunnell, C., Vahdat, L., Schwartzberg, L., et al.[2016]

The compound 109881 is a promising taxoid being developed to treat taxoid-resistant solid tumors, including brain and lung cancers, and can be administered both orally and intravenously.

As of May 2001, 109881 was undergoing phase IIa clinical trials in multiple countries, indicating its potential efficacy and safety in treating resistant cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

109881 Aventis. Ojima, I., Geney, R.[2007]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

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

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

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

New Approved Use for Keytruda. [2022]

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

A Randomized, Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407. [2021]

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

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

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

FDA Approves Pembrolizumab for BCG-Unresponsive NMIBC. [2021]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Phase I trial of ixabepilone plus pegylated liposomal doxorubicin in patients with adenocarcinoma of breast or ovary. [2021]

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

Identification of key genes and specific pathways potentially involved in androgen-independent, mitoxantrone-resistant prostate cancer. [2022]

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

Phase I/II study of ixabepilone plus capecitabine in anthracycline-pretreated/resistant and taxane-resistant metastatic breast cancer. [2016]

13. England pubmed.ncbi.nlm.nih.gov

109881 Aventis. [2007]