Ipatasertib + Docetaxel for Non-Small Cell Lung Cancer

(Ipat-Lung Trial)

Recruiting at 4 trial locations

Overseen By KUCC Navigator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Jun Zhang, MD, PhD

Must not be taking: Investigational agents, Strong CYP3A4 inhibitors

Disqualifiers: Targetable mutations, Uncontrolled brain metastasis, Diabetes, 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 12 months

60 Participants Needed

Trial Summary

What is the purpose of this trial?

For metastatic/advanced NSCLC patients who do not have targetable mutations, either immunotherapy targeting the programmed death-1 and its ligand (PD-1/L1) pathway alone or in combination with platinum doublet chemotherapy is now a standard of care. However, still about half of the patients do not benefit due to treatment resistance. It is therefore critically important to find novel therapies and combinations to benefit patients who have failed or are intolerant to 1st line immunotherapy. This study hypothesizes that ipatasertib in combination with taxane (e.g. docetaxel) can be an effective strategy. Ipatasertib is a novel adenosine triphosphate (ATP)-competitive inhibitor that has demonstrated robust and selective targeting of protein kinase B (PKB, also known as AKT) in cancer patients. Importantly, evidence from preclinical studies has demonstrated that AKT inhibitors (e.g. ipatasertib) can enhance the therapeutic effect of chemotherapy as well as immunotherapy via modulating Phosphatidylinositol 3-kinase (PI3'K)-AKT activity.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot be on other cancer treatments or certain medications that affect liver enzymes 14 days before and during the study.

What data supports the effectiveness of the drug combination Ipatasertib and Docetaxel for treating non-small cell lung cancer?

Ipatasertib, when combined with other chemotherapy drugs like paclitaxel, has shown to improve progression-free survival in breast cancer patients, suggesting potential benefits when combined with chemotherapy for other cancers. Additionally, ipatasertib has been studied for its safety and effectiveness in various solid tumors, indicating it may be beneficial in combination therapies. ^{1 2 3 4 5}

What is known about the safety of Ipatasertib in humans?

Ipatasertib has been studied for safety in various cancers, including prostate cancer, where it was generally well-tolerated but had some manageable side effects. It has been tested alone and with other drugs, showing a safety profile that includes dose-limiting toxicities and maximum tolerated doses. ^{1 5 6 7 8}

What makes the drug Ipatasertib + Docetaxel unique for treating non-small cell lung cancer?

The combination of Ipatasertib, a drug that targets specific cancer cell growth pathways, with Docetaxel, a chemotherapy drug that disrupts cell division, offers a novel approach by potentially enhancing the effectiveness of treatment through dual mechanisms of action, which is different from standard chemotherapy regimens. ^{9 10 11 12 13}

Research Team

Jun Zhang, MD, PhD

Principal Investigator

The University of Kansas

Eligibility Criteria

This trial is for adults over 18 with advanced/metastatic non-small cell lung cancer (NSCLC) who didn't respond to first-line anti-PD1/PD-L1 therapy. They should have a life expectancy of at least 12 weeks, be in good physical condition (ECOG 0 or 1), and not have any targetable mutations for other therapies. Participants must use contraception and cannot be pregnant, breastfeeding, or planning to donate sperm.

Inclusion Criteria

I am 18 years old or older.

You have a measurable disease according to specific guidelines.

I agree not to donate sperm during and for 3 months after the study.

Exclusion Criteria

I have or had inflammatory bowel disease or active bowel inflammation.

Psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent

Any condition that, in the opinion of the investigator, would interfere with evaluation or interpretation of patient safety or study results

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ipatasertib and docetaxel in 21-day cycles, with ipatasertib administered orally for 14 days and docetaxel intravenously on day 1 of each cycle

up to 12 months

1 visit every 21 days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 12 months

Treatment Details

Interventions

• Ipatasertib

Trial Overview The study tests ipatasertib combined with docetaxel in patients whose NSCLC has progressed despite immunotherapy. Ipatasertib targets the AKT protein kinase which may enhance chemotherapy and immunotherapy effects by modulating PI3'K-AKT activity.

Participant Groups

Group I: Treatment Experimental Treatment 1 Intervention

Ipatasertib, 400 mg once daily, Oral, Days 1-14 of each 21 day cycle (2 weeks on and 1 week off). Docetaxel, 75 mg/m2, Intra-venous, Day 1 of each 21 day cycle.

Who Is Running the Clinical Trial?

Jun Zhang, MD, PhD

Lead Sponsor

Trials

5

Recruited

220+

University of Iowa

Collaborator

Trials

486

Recruited

934,000+

University of Kentucky

Collaborator

Trials

198

Recruited

224,000+

Findings from Research

Ipatasertib was found to be safe and tolerable in Japanese patients with solid tumors, with a maximum tolerated dose (MTD) of 600 mg/day when used alone and a maximum administered dose (MAD) of 400 mg/day when combined with abiraterone and prednisolone.

The study showed that ipatasertib led to stable disease in 53.3% of patients receiving it as monotherapy, and in combination with other treatments, one patient achieved a complete response, indicating potential efficacy in managing solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of ipatasertib as a single agent and in combination with abiraterone plus prednisolone in Japanese patients with advanced solid tumors. Doi, T., Fujiwara, Y., Matsubara, N., et al.[2023]

The combination of the AKT inhibitor ipatasertib with paclitaxel significantly improved progression-free survival in patients with metastatic triple-negative breast cancer, especially in those with specific genetic alterations (PIK3CA/AKT1/PTEN).

Circulating tumor DNA (ctDNA) analysis showed that lower levels of ctDNA during treatment were associated with better outcomes, indicating that ctDNA could be a useful tool for monitoring treatment response and prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating Tumor DNA and Biomarker Analyses From the LOTUS Randomized Trial of First-Line Ipatasertib and Paclitaxel for Metastatic Triple-Negative Breast Cancer. Wongchenko, MJ., Kim, SB., Saura, C., et al.[2022]

In a phase Ib trial involving 51 patients with metastatic castration-resistant prostate cancer (mCRPC), the combination of ipatasertib and rucaparib was found to be manageable, with a recommended phase II dose established, but resulted in a modest prostate-specific antigen (PSA) response rate of only 26%.

While the treatment was associated with significant adverse events (46% of patients experienced grade 3/4 events), there were no deaths, and the median overall survival was reported at 13.3 months, indicating that while the combination was tolerable, it did not show strong antitumor activity in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib, Open-label Study Evaluating the Safety and Efficacy of Ipatasertib plus Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer. Pook, D., Geynisman, DM., Carles, J., et al.[2023]

In a trial involving 385 patients with advanced non-small cell lung cancer (NSCLC), the combination of ganetespib and docetaxel showed an acceptable safety profile, with neutropenia being the most common severe side effect, affecting 41% of patients in the combination group.

Although the primary endpoints for progression-free survival (PFS) were not met in the overall population, significant benefits were observed in patients diagnosed with advanced adenocarcinoma more than 6 months prior, indicating potential for this subgroup to benefit from the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1). Ramalingam, S., Goss, G., Rosell, R., et al.[2020]

The phase Ib study involving 122 patients demonstrated that the oral AKT inhibitor ipatasertib, when combined with chemotherapy or hormonal therapy, was generally well tolerated, with a safety profile similar to other AKT inhibitors, although some specific adverse effects like diarrhea and hyperglycemia were noted.

The recommended phase II doses for ipatasertib were established at 600 mg with mFOLFOX6 and 400 mg with paclitaxel, indicating a manageable safety profile and potential for further clinical evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of ipatasertib combined with chemotherapy: results from a phase Ib study in solid tumors. Isakoff, SJ., Tabernero, J., Molife, LR., et al.[2021]

Ipatasertib, a selective AKT kinase inhibitor being developed for solid tumors, showed increased bioavailability and exposure after multiple dosing in a study involving 342 cancer patients, indicating its pharmacokinetic profile can improve with continued use.

Factors such as age and weight affect the drug's clearance and bioavailability, but the changes in exposure are small and unlikely to be clinically significant, suggesting that ipatasertib can be safely administered across a range of patient demographics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Ipatasertib and Its Metabolite in Cancer Patients. Yoshida, K., Wilkins, J., Winkler, J., et al.[2022]

In the IPATential150 trial involving 1097 patients with metastatic castration-resistant prostate cancer, adding ipatasertib to abiraterone and prednisone significantly improved radiographic progression-free survival for patients with PTEN-loss tumors.

While ipatasertib was associated with a higher rate of serious adverse events and treatment discontinuation compared to placebo, its overall safety profile was considered tolerable, suggesting that with proper management, the side effects could be mitigated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Profile of Ipatasertib Plus Abiraterone vs Placebo Plus Abiraterone in Metastatic Castration-resistant Prostate Cancer. Matsubara, N., de Bono, J., Sweeney, C., et al.[2023]

In a study of 1101 patients with metastatic castration-resistant prostate cancer, ipatasertib showed a significant correlation between drug exposure and improved survival specifically in patients with PTEN-loss tumors, indicating its potential efficacy in this subgroup.

While ipatasertib treatment was associated with improved radiographic progression-free survival, higher drug exposure also correlated with increased risks of adverse events, such as serious adverse events and hyperglycemia, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of exposure-response relationships of ipatasertib in patients with metastatic castration-resistant prostate cancer in the IPATential150 study. Kotani, N., Wilkins, JJ., Wade, JR., et al.[2022]

In a study of 128 patients with previously treated non-small cell lung cancer (NSCLC), the combination of nivolumab and docetaxel significantly improved overall survival (OS) to 23.1 months compared to 14.7 months with nivolumab alone.

The combination therapy also resulted in a longer progression-free survival (PFS) of 6.7 months versus 3.1 months for nivolumab alone, although it was associated with higher rates of hematotoxicity and gastrointestinal adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Comparison of Nivolumab versus Nivolumab + Docetaxel for Previously Treated Advanced or Recurrent ICI-Naïve Non-Small Cell Lung Cancer: TORG1630. Taniguchi, Y., Shimokawa, T., Takiguchi, Y., et al.[2023]

The combination of docetaxel and irinotecan as a first-line treatment for advanced non-small-cell lung cancer (NSCLC) showed a moderate overall response rate of 36.4% among 22 chemotherapy-naive patients, with a median overall survival of 10 months.

The treatment was associated with significant toxicities, primarily grade 3-4 diarrhea and neutropenia, including one case of neutropenic sepsis leading to death, suggesting that while the regimen may benefit certain patients, careful monitoring for side effects is essential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel and irinotecan as first-line chemotherapy in patients with advanced non-small-cell lung cancer: a pilot study. Abou-Mourad, Y., Otrock, ZK., Makarem, JA., et al.[2018]

Docetaxel is an effective treatment for non-small cell lung cancer (NSCLC), showing comparable efficacy to newer platinum-based therapies in advanced stages, and has been approved for use in this context.

Clinical trials are ongoing to explore the best ways to combine docetaxel with other treatments, such as thoracic radiotherapy and molecularly targeted agents, to enhance its effectiveness in various stages of NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel in non-small cell lung cancer: a review. Davies, AM., Lara, PN., Mack, PC., et al.[2019]

Docetaxel is recognized as one of the most effective cytotoxic drugs for treating non-small cell lung cancer, with ongoing clinical investigations exploring its use in combination therapies and radiotherapy.

Current studies at our hospital include trials combining docetaxel with gemcitabine and ifosfamide, as well as a planned randomized study to evaluate its effectiveness in conjunction with chemoradiotherapy for patients with inoperable stage III non-small cell lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel (Taxotere) in non-small cell lung cancer: ongoing studies in Heidelberg and future plans. Manegold, C.[2022]

In a phase II trial involving 28 patients with advanced non-small cell lung cancer, the combination of docetaxel and capecitabine resulted in a low overall response rate of only 18%, which did not meet the pre-specified target of 50%, leading to the trial's termination.

The study found that lower levels of dihydropyrimidine dehydrogenase (DPD) in patients were associated with better responses to treatment, but these lower DPD levels also correlated with higher rates of severe side effects, indicating a potential trade-off between efficacy and toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of modulated-capecitabine and docetaxel in chemonaive patients with advanced non-small cell lung cancer (NSCLC). Bertino, EM., Bekaii-Saab, T., Fernandez, S., et al.[2021]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Phase I study of ipatasertib as a single agent and in combination with abiraterone plus prednisolone in Japanese patients with advanced solid tumors. [2023]

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

Circulating Tumor DNA and Biomarker Analyses From the LOTUS Randomized Trial of First-Line Ipatasertib and Paclitaxel for Metastatic Triple-Negative Breast Cancer. [2022]

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

A Phase Ib, Open-label Study Evaluating the Safety and Efficacy of Ipatasertib plus Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer. [2023]

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

A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1). [2020]

5. England pubmed.ncbi.nlm.nih.gov

Antitumor activity of ipatasertib combined with chemotherapy: results from a phase Ib study in solid tumors. [2021]

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

Population Pharmacokinetics of Ipatasertib and Its Metabolite in Cancer Patients. [2022]

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

Safety Profile of Ipatasertib Plus Abiraterone vs Placebo Plus Abiraterone in Metastatic Castration-resistant Prostate Cancer. [2023]

8. Germany pubmed.ncbi.nlm.nih.gov

Characterization of exposure-response relationships of ipatasertib in patients with metastatic castration-resistant prostate cancer in the IPATential150 study. [2022]

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

A Randomized Comparison of Nivolumab versus Nivolumab + Docetaxel for Previously Treated Advanced or Recurrent ICI-Naïve Non-Small Cell Lung Cancer: TORG1630. [2023]

10. Lebanon pubmed.ncbi.nlm.nih.gov

Docetaxel and irinotecan as first-line chemotherapy in patients with advanced non-small-cell lung cancer: a pilot study. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Docetaxel in non-small cell lung cancer: a review. [2019]

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

Docetaxel (Taxotere) in non-small cell lung cancer: ongoing studies in Heidelberg and future plans. [2022]

13. Ireland pubmed.ncbi.nlm.nih.gov

A phase II study of modulated-capecitabine and docetaxel in chemonaive patients with advanced non-small cell lung cancer (NSCLC). [2021]