ARRY-614 + Immune Checkpoint Inhibitors for Cancer

Overseen By Amy Rose, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Dan Zandberg

Must be taking: Nivolumab, Ipilimumab

Must not be taking: Systemic steroids

Disqualifiers: Active autoimmune disease, Brain metastases, Active infection, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of combining ARRY-614, an experimental treatment, with immune checkpoint inhibitors like nivolumab and ipilimumab to treat certain advanced cancers. It focuses on patients with advanced solid tumors, including melanoma (a type of skin cancer), NSCLC (a type of lung cancer), HNSCC (a type of head and neck cancer), and RCC (a type of kidney cancer). Individuals who have experienced cancer growth despite previous treatments and seek new options might be suitable for this trial. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants a chance to be among the first to receive this new treatment.

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 have received systemic anticancer therapy or an investigational agent within 2 weeks prior to the trial, and there is a 4-week washout period for prior immune-based anticancer therapy.

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

Studies have shown that combining ARRY-614 with immune system drugs like nivolumab and ipilimumab is generally safe. In earlier research, patients with advanced solid tumors who took ARRY-614 with nivolumab, or with both nivolumab and ipilimumab, controlled their disease without unexpected side effects. The evidence suggests that this treatment combination is manageable for patients.

While some side effects can occur, as with any treatment, they were mostly mild to moderate. Most patients tolerated the treatment well, and the side effects were not severe enough to discontinue the treatment.

This trial remains in the early stages, so researchers continue to closely monitor its safety. However, the initial findings are promising in terms of safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ARRY-614 combined with immune checkpoint inhibitors like nivolumab and ipilimumab because it offers a novel approach to treating cancers such as melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Unlike standard treatments that might solely target tumor cells, this combination boosts the immune system's ability to recognize and attack cancer cells more effectively. ARRY-614 works by inhibiting specific pathways that help cancer evade the immune system, while nivolumab and ipilimumab enhance the immune response against tumors. This multi-faceted attack has the potential to improve outcomes for patients with advanced solid tumors, where current options can be limited.

What evidence suggests that this trial's treatments could be effective for cancer?

Research shows that ARRY-614, when combined with nivolumab, may help treat advanced solid tumors. In this trial, some participants will receive ARRY-614 with nivolumab, while others will receive ARRY-614 with both nivolumab and ipilimumab. Previous studies found that some patients experienced tumor shrinkage, while others maintained stable disease, meaning their cancer did not grow. Additionally, combining ARRY-614 with both nivolumab and ipilimumab has been well-tolerated and helped control the disease in many cases. Ipilimumab and nivolumab are already effective for advanced melanoma, which suggests promise for this combination with ARRY-614. These findings indicate that adding ARRY-614 could enhance the effects of these immune therapies for certain cancers. ^{5 6 7 8 9}

Who Is on the Research Team?

Dan Zandberg, MD

Principal Investigator

UPMC Hillman Cancer Center

Are You a Good Fit for This Trial?

Adults with certain advanced cancers (like lung, kidney, melanoma) who can receive nivolumab or ipilimumab therapy. They should have a life expectancy of at least 3 months and be willing to undergo biopsies if needed. Participants must not be pregnant, breastfeeding, or have severe heart issues, active brain metastases requiring steroids, recent major surgery without recovery, significant cardiac disease within the past 6 months, active autoimmune diseases treated in the last 2 years, other primary active cancers needing treatment, known hepatitis B/C infections or hypersensitivity to trial drugs.

Inclusion Criteria

You are expected to live for at least 3 more months.

My tumor can be easily biopsied, and I agree to have two biopsies.

Be able to understand and willing to sign the informed consent form

Exclusion Criteria

I have another type of cancer that needs treatment.

I have a condition that affects how my body absorbs medication taken by mouth.

I do not have an active infection needing antibiotics or a fever over 38.5°C in the last week.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase Ib Treatment

Participants receive ARRY-614 in combination with nivolumab or nivolumab+ipilimumab to determine safety and tolerability

3-4 weeks per cycle

Continuous cycles

Phase II Treatment

Participants receive ARRY-614 in combination with nivolumab or nivolumab+ipilimumab to estimate efficacy

3-4 weeks per cycle

Continuous cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 48 months

What Are the Treatments Tested in This Trial?

Interventions

• ARRY-614
• Ipilimumab, Nivolumab
• Nivolumab

Trial Overview The study is testing ARRY-614 combined with either nivolumab alone or plus ipilimumab in two phases: Phase Ib for safety and dosage determination and Phase II for efficacy estimation in patients with NSCLC (non-small cell lung cancer), HNSCC (head and neck squamous cell carcinoma), RCC (renal cell carcinoma), and melanoma.

How Is the Trial Designed?

Group I: Phase Ib ARRY-614 + nivolumab + ipilimumab Experimental Treatment 1 Intervention

Participants with advanced solid tumors will received ARRY-614 in combination with nivolumab + ipilimumab. (histologically confirmed metastatic or unresectable malignancy with lacking curative measures; nivolumab and ipilimumab must be available and appropriate for proposed therapy)

Group II: Phase Ib ARRY-614 + nivolumab Experimental Treatment 1 Intervention

Participants with advanced solid tumors will receive ARRY-614 in combination with nivolumab. (histologically confirmed metastatic or unresectable malignancy with lacking curative measures; nivolumab must be available and appropriate for proposed therapy)

Group III: Phase II ARRY-614 + nivolumab + ipilimumab (melanoma) Experimental Treatment 1 Intervention

Participants with melanoma will receive ARRY-614 combined with nivolumab + ipilimumab.

Group IV: Phase II ARRY-614 + nivolumab + ipilimumab (RCC) Experimental Treatment 1 Intervention

Participants with RCC will receive ARRY-614 combined with nivolumab + ipilimumab.

Group V: Phase II ARRY-614 + nivolumab Experimental Treatment 1 Intervention

Participants with of NSCLC and HNSCCC will receive ARRY-614 combined with nivolumab.

Who Is Running the Clinical Trial?

Dan Zandberg

Lead Sponsor

Trials

7

Recruited

330+

Jason J. Luke, MD

Lead Sponsor

Trials

5

Recruited

720+

Array BioPharma

Industry Sponsor

Trials

29

Recruited

1,400+

Published Research Related to This Trial

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

In a study of 47 patients with metastatic renal cell carcinoma treated with nivolumab, 48.9% experienced immune-related adverse events (irAEs), with rash being the most common.

Patients who developed irAEs had significantly longer progression-free survival (13.1 months vs. 4.87 months) and overall survival (26.0 months vs. not reached) compared to those without irAEs, indicating that the presence of irAEs may be a positive prognostic factor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between immune-related adverse events and prognosis in patients with metastatic renal cell carcinoma treated with nivolumab. Ishihara, H., Takagi, T., Kondo, T., et al.[2020]

Nivolumab showed antitumor activity in patients with metastatic renal cell carcinoma (mRCC), with median overall survival rates of 18.2, 25.5, and 24.7 months across three different doses, indicating its potential effectiveness as a treatment option.

The safety profile of nivolumab was manageable, with fatigue being the most common side effect; however, no significant dose-response relationship was found in terms of progression-free survival, suggesting that the efficacy may not increase with higher doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. Motzer, RJ., Rini, BI., McDermott, DF., et al.[2022]

Nivolumab is a PD-1 immune checkpoint inhibitor that effectively enhances antitumor immunity by blocking the PD-1 receptor on activated T cells, which helps reverse immune suppression in cancer patients.

Clinical trials have demonstrated the efficacy of nivolumab in treating various cancers, including non-small-cell lung cancer, melanoma, and renal cell carcinoma, making it a promising option in targeted immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab as Programmed Death-1 (PD-1) Inhibitor for Targeted Immunotherapy in Tumor. Guo, L., Zhang, H., Chen, B.[2022]

Nivolumab, administered at 3 mg/kg with or without a peptide vaccine, was well tolerated and demonstrated a 25% response rate in patients with advanced melanoma, regardless of prior ipilimumab treatment.

The study suggests that nivolumab can induce long-lasting responses, with some patients responding for up to 140 weeks, and highlights the potential for combining or sequencing nivolumab with ipilimumab for better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. Weber, JS., Kudchadkar, RR., Yu, B., et al.[2022]

In a study of 53 patients with metastatic renal cell carcinoma treated with nivolumab, those who experienced immune-related adverse events (irAEs) had significantly better overall survival compared to those without irAEs, indicating a potential link between irAEs and treatment efficacy.

The study found that a lower platelet-to-lymphocyte ratio before treatment was a risk factor associated with the development of irAEs, suggesting that this ratio could be a useful predictor for monitoring patient responses to nivolumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Immune-related Adverse Events and Clinical Outcome Following Nivolumab Treatment in Patients With Metastatic Renal Cell Carcinoma. Kobayashi, K., Iikura, Y., Hiraide, M., et al.[2021]

In a study of 46 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab, 72% experienced immune-related adverse events (irAEs), which were linked to significantly longer progression-free survival (PFS) compared to those without irAEs.

While irAE development was an independent predictor of longer PFS, it did not affect overall survival (OS), suggesting that irAEs could serve as a useful prognostic marker for treatment outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic impact of immune-related adverse events in metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. Ikeda, T., Ishihara, H., Nemoto, Y., et al.[2022]

Nivolumab is shown to be the most cost-effective treatment option for advanced melanoma patients in England, with incremental cost-effectiveness ratios of £24,483 for BRAF mutation-negative and £17,362 for mutation-positive patients.

The analysis utilized a Markov state-transition model based on patient-level data from clinical trials, indicating that nivolumab provides long-term survival benefits while being economically favorable compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. Meng, Y., Hertel, N., Ellis, J., et al.[2020]

In a study analyzing 2,088 individual case safety reports (ICSRs) related to immune checkpoint inhibitors (ICIs) in Italy, 801 reports documented serious immune-related adverse drug reactions (irADRs), primarily affecting male patients with gastrointestinal and skin toxicities.

Among the ICIs, nivolumab and pembrolizumab were most frequently associated with irADRs, with significant risks identified for pembrolizumab and ipilimumab, highlighting the need for oncologists to recognize and manage these serious side effects effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors and Immune-Related Adverse Drug Reactions: Data From Italian Pharmacovigilance Database. Ruggiero, R., Fraenza, F., Scavone, C., et al.[2022]

In a study of 37 patients with stage IV metastatic melanoma, high levels of soluble CD73 (sCD73) enzyme activity in the serum were linked to significantly poorer overall survival and progression-free survival when treated with nivolumab.

Patients with high sCD73 activity had a median progression-free survival of only 2.6 months compared to 14.2 months for those with lower activity, suggesting that measuring sCD73 could help predict how well patients will respond to nivolumab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab. Morello, S., Capone, M., Sorrentino, C., et al.[2018]

In a pooled analysis of 1332 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab showed a median overall survival (OS) of 18.6 months and a 3-year OS rate of 35%, indicating significant long-term survival benefits compared to traditional chemotherapy.

The study found that patients who responded to treatment at 6 months had markedly better survival rates, with a 3-year OS of 66% for responders, highlighting the importance of early response in predicting long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Borghaei, H., Ciuleanu, TE., Lee, JS., et al.[2023]

Nivolumab, an anti-PD-1 antibody, was administered to a 63-year-old female patient with metastatic melanoma after renal transplantation, highlighting the potential for anti-tumor activity in high-risk patients, despite the challenges of concurrent immunosuppression.

The patient experienced acute renal allograft rejection and renal failure shortly after starting nivolumab, indicating significant risks associated with this treatment in transplant recipients, but she later showed a positive clinical response after re-challenging with nivolumab while on hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. Ong, M., Ibrahim, AM., Bourassa-Blanchette, S., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04074967?term=AREA%5BBasicSearch%5D(nivolumab%20and%20ipilimumab)%20AND%20AREA%5BOverallStatus%5D(NOT_YET_RECRUITING%20OR%20RECRUITING%20OR%20ACTIVE_NOT_RECRUITING%20OR%20COMPLETED)%20AND%20AREA%5BPhase%5D(PHASE2%20OR%20PHASE3)&rank=1

NCT04074967 | Study of ARRY-614 Plus Either Nivolumab ... In this study, the Phase Ib portion aims to establish safety and tolerability of ARRY-614 with either nivolumab or ipilimumab and to determine a recommended ...

2. dana-farber.org dana-farber.org/clinical-trials/21-377

A Phase Ib/II study of ARRY-614 plus either nivolumab or ... In this study, the Phase Ib portion aims to establish safety and tolerability of ARRY-614 with either nivolumab or ipilimumab and to determine a recommended ...

3. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04074967/

Clinical Trial: NCT04074967 The Phase II portion will estimate the efficacy of ARRY-614 in combination with either nivolumab or ipilimumab immunotherapy in patients with ...

4. clin.larvol.com clin.larvol.com/trial-detail/NCT04074967

Study of ARRY-614 Plus Either Nivolumab or ... Of the 20 evaluable patients, 3 had partial responses (PRs), 7 achieved stable disease (SD), 2 patients had immune-related SD (irSD), and the remaining 8 ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4346216/

Nivolumab in NSCLC: latest evidence and clinical potential This review will discuss results from early phase studies of nivolumab in solid tumors including non-small cell lung cancer (NSCLC)

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04074967

NCT04074967 | Study of ARRY-614 Plus Either Nivolumab ... In this study, the Phase Ib portion aims to establish safety and tolerability of ARRY-614 with either nivolumab or ipilimumab and to determine a recommended ...

7. onclive.com onclive.com/view/arry-614-plus-immune-checkpoint-inhibition-can-induce-durable-responses-in-advanced-solid-tumors

ARRY-614 Plus Immune Checkpoint Inhibition Can Induce ... The combination of the p38 MAPK inhibitor ARRY-614 plus nivolumab with or without ipilimumab was well tolerated and elicited disease control.

8. jitc.bmj.com jitc.bmj.com/content/10/Suppl_2/A615

588 Phase Ib study of the p38 inhibitor ARRY-614 with ... Here we report on the safety and anti-tumor activity of ARRY-614 with nivolumab (N), ipilimumab (I), or N+I in human subjects with advanced solid tumors.

9. ctv.veeva.com ctv.veeva.com/study/study-of-arry-614-plus-either-nivolumab-or-nivolumab-ipilimumab

Study of ARRY-614 Plus Either Nivolumab or Nivolumab+ ... In this study, the Phase Ib portion aims to establish safety and tolerability of ARRY-614 with either nivolumab or ipilimumab and to ...