NKT3447 for Advanced Cancer

Recruiting at 7 trial locations

Overseen By Andrae Vandross, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Waitlist Available

Sponsor: NiKang Therapeutics, Inc.

Must not be taking: CDK2 inhibitors

Disqualifiers: Curative candidates, Visceral crisis, HIV, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

The goal of the Dose Escalation phase of the study is to evaluate the safety, tolerability, and pharmacokinetics (PK) to determine the maximum tolerated dose (MTD) and/or preliminary recommended dose for expansion (RDE) of NKT3447 in adults with advanced or metastatic solid tumors. The goal of the Expansion phase of the study is to evaluate the safety, tolerability, pharmacokinetics (PK), and the preliminary antitumor activity of NKT3447 in adult subjects with cyclin E1 (CCNE1) amplified ovarian cancer at the RDEs selected in Dose Escalation and to determine the preliminary recommended phase 2 dose (RP2D).

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What safety information is available for NKT3447 or similar treatments in humans?

In a study of a similar treatment, NKT-01, some side effects like mild nausea, vomiting, and low blood pressure were observed, especially at higher doses. More serious effects like low blood cell counts were also noted but usually returned to normal after about three weeks. ^{1 2 3 4 5}

What makes the drug NKT3447 unique for treating advanced cancer?

NKT3447 is unique because it targets the PI3K/AKT/mTOR signaling pathway, which is often activated in advanced cancers. This pathway is crucial for cell growth and survival, and targeting it can be particularly effective in patients with specific genetic mutations like PIK3CA H1047R, which may predict a better response to this type of treatment. ^{6 7 8 9 10}

Eligibility Criteria

Adults with advanced or metastatic solid tumors, including various types of cancer such as breast, ovarian, endometrial, stomach, and small cell lung cancer. Specifically looking for participants with CCNE1 amplified ovarian cancer for the expansion phase.

Inclusion Criteria

My cancer type is eligible for the dose escalation study.

My ovarian cancer is resistant to platinum treatment and has cyclin E amplification.

My cancer is advanced, cannot be surgically removed, and has not improved with standard treatments.

Exclusion Criteria

I have previously been treated with CDK2, WEE1, or PKMYT1 inhibitors.

My solid tumor can potentially be cured with surgery, radiation, or chemotherapy.

I still feel side effects from my previous cancer treatment, but they are mild.

Treatment Details

Interventions

• NKT3447 (Cancer Vaccine)

Trial Overview NKT3447 is being tested to find out its safety and tolerability at different doses (Dose Escalation phase) and to see how well it works against certain cancers like CCNE1 amplified ovarian cancer (Expansion phase).

Participant Groups

Group I: Dose Expansion Experimental Treatment 1 Intervention

Dose expansion will include 2 RDEs selected to determine the preliminary antitumor activity and the RP2D.

Group II: Dose Escalation Experimental Treatment 1 Intervention

Dose escalation will assess the safety, efficacy, and PK/PD data of oral dosing NKT3447 at increasing dosage levels to determine the MTD and/or preliminary RDEs.

Who Is Running the Clinical Trial?

NiKang Therapeutics, Inc.

Lead Sponsor

Trials

5

Recruited

1,000+

Findings from Research

In a phase I study involving 43 patients with advanced solid tumors, MEDI-573 demonstrated a favorable safety profile with no dose-limiting toxicities and only one case of treatment-related hyperglycemia.

While MEDI-573 did not lead to any partial or complete responses in the tumors, 13 out of 39 evaluable patients showed stable disease, indicating some preliminary antitumor activity in a heavily pretreated population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I dose-escalation study of MEDI-573, a bispecific, antiligand monoclonal antibody against IGFI and IGFII, in patients with advanced solid tumors. Haluska, P., Menefee, M., Plimack, ER., et al.[2021]

In a phase I study involving 38 patients with various malignancies, NKT-01 (deoxyspergualin) was administered intravenously, showing no clear adverse effects at single doses up to 320 mg/m2, but dose-dependent toxicities such as myelosuppression and nausea were observed during daily administration.

A significant reduction in leukemic cells was noted in one patient with adult T-cell leukemia, suggesting potential efficacy, while the recommended dose for further studies was set at 400 mg/m2 for solid tumors, indicating a need for careful monitoring of hematological toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of NKT-01. Tamura, K., Niitani, H., Oguro, M., et al.[2018]

The maximum-tolerated dose (MTD) of SB-743921 was established at 4 mg/m², with neutropenia being the most common dose-limiting toxicity observed in a study involving 44 patients with advanced solid tumors or relapsed/refractory lymphoma.

One patient experienced a durable objective response lasting 11 months, and 6 patients had stable disease for over four treatment cycles, indicating promising efficacy and a favorable safety profile for further development of SB-743921.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose. Holen, KD., Belani, CP., Wilding, G., et al.[2021]

The study found that an oral drug combining paclitaxel and HM30181A is well tolerated in patients with advanced cancers, with only one case of significant toxicity (grade 3 neutropenia) reported at a dose of 240 mg/m².

The recommended phase II dose for this combination therapy is 300 mg/m² of paclitaxel, which effectively achieves the desired plasma concentration for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer. Lee, HJ., Heo, DS., Cho, JY., et al.[2021]

In a study of 1864 advanced ovarian cancer patients, 71% experienced neurotoxicity (NT) during treatment, particularly affecting older patients and those with lower quality of life scores.

Switching from paclitaxel to docetaxel did not show any significant improvement in NT symptoms, with similar rates of worsening NT reported for both drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurotoxicity in ovarian cancer patients on Gynecologic Oncology Group (GOG) protocol 218: characteristics associated with toxicity and the effect of substitution with docetaxel: an NRG Oncology/Gynecologic Oncology Group study. Chase, DM., Huang, H., Foss, CD., et al.[2018]

In a study of 1,012 cancer patients, 10% had PIK3CA mutations, and those with the H1047R mutation showed a significantly higher partial response rate (38%) to PI3K/AKT/mTOR inhibitors compared to other mutation types and wild-type patients.

Patients with coexisting PIK3CA and KRAS mutations did not achieve any partial responses, indicating that the presence of KRAS mutations may negatively impact the efficacy of these targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials. Janku, F., Wheler, JJ., Naing, A., et al.[2022]

The combination of EPI-002, an antagonist targeting the N-terminal domain of the androgen receptor, with mTOR inhibitors like BEZ235 showed significant antitumor activity in enzalutamide-resistant prostate cancer cells, indicating a promising therapeutic strategy for castration-resistant prostate cancer (CRPC).

This dual targeting approach effectively reduced the expression of AR-V target genes and inhibited tumor growth in both in vitro and in vivo models, suggesting that blocking both the androgen receptor and the PI3K/Akt/mTOR pathway can enhance treatment efficacy in advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cotargeting Androgen Receptor Splice Variants and mTOR Signaling Pathway for the Treatment of Castration-Resistant Prostate Cancer. Kato, M., Banuelos, CA., Imamura, Y., et al.[2022]

The combination of NVP-BEZ235, a dual PI3K/mTOR inhibitor, and sunitinib, a tyrosine kinase inhibitor, significantly enhances the antitumor effect in castration-resistant prostate cancer (CRPC) cells that are resistant to docetaxel, with a strong synergy indicated by a synergy volume of 182.47 μM/ml2%.

This combination therapy not only reduced the IC50 values of both drugs by 7.8-fold for NVP-BEZ235 and 6.6-fold for sunitinib but also induced caspase-dependent apoptosis in the resistant cancer cells, suggesting a promising strategy for overcoming treatment resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic antitumor effect of NVP-BEZ235 and sunitinib on docetaxel-resistant human castration-resistant prostate cancer cells. Park, HS., Hong, SK., Oh, MM., et al.[2018]

In a study of 307 triple-negative breast cancer (TNBC) patients, high levels of nuclear KIFC1 (nKIFC1) were linked to significantly worse survival outcomes specifically in African American patients, indicating its potential as a prognostic biomarker for this group.

The study found that nKIFC1 expression correlated with cell proliferation in White TNBC patients but not in African American patients, suggesting that nKIFC1 may play a different role in tumor behavior and migration in these populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-institutional study of nuclear KIFC1 as a biomarker of poor prognosis in African American women with triple-negative breast cancer. Ogden, A., Garlapati, C., Li, XB., et al.[2022]

The dual PI3K/mTOR inhibitor PF-04691502 showed over 80% inhibition of cell growth in five nasopharyngeal carcinoma (NPC) cell lines, indicating strong preclinical efficacy with IC50 values in the hundred nanomolar range.

In vivo studies demonstrated that PF-04691502 effectively reduced tumor volume and weight in a xenograft model without significant body weight loss, suggesting it is both effective and well-tolerated for potential NPC treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of the PI3K-mTOR dual inhibitor PF-04691502 as a novel therapeutic drug in nasopharyngeal carcinoma. Wong, CH., Loong, HH., Hui, CW., et al.[2022]

References

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

Phase I dose-escalation study of MEDI-573, a bispecific, antiligand monoclonal antibody against IGFI and IGFII, in patients with advanced solid tumors. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Phase I study of NKT-01. [2018]

3. Germany pubmed.ncbi.nlm.nih.gov

A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose. [2021]

4. Korea (South) pubmed.ncbi.nlm.nih.gov

A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer. [2021]

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

Neurotoxicity in ovarian cancer patients on Gynecologic Oncology Group (GOG) protocol 218: characteristics associated with toxicity and the effect of substitution with docetaxel: an NRG Oncology/Gynecologic Oncology Group study. [2018]

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

PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials. [2022]

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

Cotargeting Androgen Receptor Splice Variants and mTOR Signaling Pathway for the Treatment of Castration-Resistant Prostate Cancer. [2022]

8. Greece pubmed.ncbi.nlm.nih.gov

Synergistic antitumor effect of NVP-BEZ235 and sunitinib on docetaxel-resistant human castration-resistant prostate cancer cells. [2018]

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

Multi-institutional study of nuclear KIFC1 as a biomarker of poor prognosis in African American women with triple-negative breast cancer. [2022]

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

Preclinical evaluation of the PI3K-mTOR dual inhibitor PF-04691502 as a novel therapeutic drug in nasopharyngeal carcinoma. [2022]