Calaspargase + Cobimetinib for Pancreatic Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: OHSU Knight Cancer Institute

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Chronic pancreatitis, Cardiac disease, others

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

Compensation: Varies

Number of Visits: 9

Duration: 18 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments, calaspargase pegol-mknl (an enzyme-based therapy) and cobimetinib (a targeted therapy), to determine the safest and most effective dose for individuals with metastatic pancreatic cancer. Calaspargase pegol-mknl starves cancer cells of a necessary nutrient, while cobimetinib targets a protein that aids cancer cell growth. Together, these treatments aim to control the disease. This trial may suit those with advanced pancreatic cancer who have not found success with other standard therapies. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new therapy.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications, but you cannot use other anti-cancer therapies or certain medications like strong CYP3A inhibitors or inducers within 7 days before starting the trial. Check with the trial team for specific guidance on your medications.

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

Research shows that calaspargase pegol-mknl and cobimetinib are being tested together to assess their safety in treating pancreatic cancer. Each drug attacks cancer cells differently, but detailed safety information about their combination is still being gathered in this trial.

Calaspargase pegol-mknl is already used in other treatments and works by breaking down a nutrient essential for cancer cell growth. Cobimetinib targets a protein that aids cancer cell survival. This trial is in its early stages, focusing on determining the safest dose and understanding potential side effects.

While specific safety information for this combination isn't fully available yet, early-stage trials like this one aim to evaluate how well participants tolerate the treatment and identify any side effects. Prospective participants should discuss any concerns with the trial team to understand the potential risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about calaspargase pegol-mknl and cobimetinib for pancreatic cancer because they offer a fresh approach compared to standard treatments like chemotherapy. Calaspargase pegol-mknl is an enzyme that breaks down asparagine, an amino acid that cancer cells need to survive, which is a different mechanism than traditional chemotherapy. Cobimetinib is a MEK inhibitor that targets specific pathways cancer cells use to grow. Together, these drugs could potentially deliver a one-two punch to pancreatic cancer cells by depriving them of necessary nutrients and blocking their growth signals.

What evidence suggests that calaspargase pegol-mknl and cobimetinib might be an effective treatment for pancreatic cancer?

Research has shown that the drugs calaspargase pegol-mknl and cobimetinib might help treat pancreatic cancer. In this trial, participants will receive both calaspargase pegol-mknl and cobimetinib. Cobimetinib blocks a protein called MEK, which aids cancer cell growth. By stopping MEK, cobimetinib may slow cancer growth. Calaspargase pegol-mknl breaks down L-asparagine, a nutrient cancer cells need to survive. Together, these drugs aim to starve and stop cancer cells from growing. Early results suggest this approach might help control the disease in patients with advanced pancreatic cancer. ^{1 2 3 4 5}

Who Is on the Research Team?

Charles D. Lopez

Principal Investigator

OHSU Knight Cancer Institute

Are You a Good Fit for This Trial?

Adults with advanced or metastatic pancreatic cancer who have not responded to, cannot tolerate, or refused standard treatments like Gemcitabine-based therapy or FOLFORINOX. They must be in relatively good health (ECOG 0-2), have acceptable blood counts and organ function, and agree to use non-hormonal contraception. Pregnant women, those with certain heart conditions, severe allergies to trial drugs, uncontrolled medical issues, or recent other cancer therapies are excluded.

Inclusion Criteria

My pancreatic cancer is confirmed and has spread.

I can take care of myself and am up and about more than half of the day.

Participants of childbearing potential (POCBP) must agree to abstain from sexual intercourse or use effective non-hormonal methods of contraception starting with the first dose of study therapy through 90 days after the last dose of study therapy (because calaspargase pegol can render hormonal contraceptives ineffective)

Exclusion Criteria

I am allergic to calaspargase pegol-mknl, cobimetinib, or similar drugs.

I am not taking any strong or moderate drugs that affect liver enzymes.

My high blood pressure is not under control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive calaspargase pegol-mknl IV over 1 hour on day 1 and cobimetinib PO QD on days 1-14. Treatment repeats every 21 days for up to 6 cycles.

18 weeks

6 cycles, each with 1 in-person visit

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Follow-up visits at 3 and 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Calaspargase Pegol-mknl
• Cobimetinib

Trial Overview The trial is testing the combination of Calaspargase Pegol-mknl and Cobimetinib for safety and optimal dosing against pancreatic cancer that has spread. Calaspargase Pegol-mknl deprives cancer cells of a needed amino acid while Cobimetinib blocks a protein that helps these cells grow.

How Is the Trial Designed?

Group I: Treatment (calaspargase pegol-mknl, cobimetinib) Experimental Treatment 3 Interventions

Patients receive calaspargase pegol-mknl IV over 1 hour on day 1 and cobimetinib PO QD on days 1-14. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo a biopsy 14 days prior to starting therapybefore cycle 1, day 1 and again on day 14 of cycle 2, day 15 per the investigator's discretion, with an additional optional biopsy at the time of disease progression.

Calaspargase Pegol-mknl is already approved in European Union, United States for the following indications:

Approved in European Union as Besponsa for:

• Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)

Approved in United States as Besponsa for:

• Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients 1 year and older

Who Is Running the Clinical Trial?

OHSU Knight Cancer Institute

Lead Sponsor

Trials

239

Recruited

2,089,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Servier Pharmaceuticals, LLC

Collaborator

Trials

2

Recruited

20+

Oregon Health and Science University

Collaborator

Trials

1,024

Recruited

7,420,000+

Published Research Related to This Trial

The combination of gemcitabine, capecitabine, bevacizumab, and erlotinib showed promising efficacy in treating advanced pancreatic cancer, with 10 partial responses observed among 20 patients and median overall survival of 12.5 months.

The maximum-tolerated dose of capecitabine was determined to be 1,660 mg/m², with a recommended dose of 1,440 mg/m² for further studies, while the treatment was generally well-tolerated with manageable side effects like diarrhea and skin rash.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose finding and early efficacy study of gemcitabine plus capecitabine in combination with bevacizumab plus erlotinib in advanced pancreatic cancer. Starling, N., Watkins, D., Cunningham, D., et al.[2022]

A study of 5465 patients with advanced pancreatic cancer in Ontario showed that the introduction of new chemotherapy regimens, GEMNAB and FOLFIRINOX, significantly improved overall survival rates over time, with median survival increasing from 5.6 months to 7.6 months between 2008 and 2018.

FOLFIRINOX was found to provide better overall survival compared to GEMNAB, particularly in younger and healthier patients, while GEMNAB still showed improved survival compared to the older standard treatment, gemcitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Association of Drug-Funding Reimbursement With Survival Outcomes and Use of New Systemic Therapies Among Patients With Advanced Pancreatic Cancer. Raphael, MJ., Raskin, W., Habbous, S., et al.[2023]

In a study of 53 patients with inoperable or metastatic pancreatic cancer, the combination of gemcitabine (GEM) and capecitabine (CAP) resulted in an 18.9% rate of objective partial responses and a median overall survival of 8 months, indicating its potential efficacy as a treatment option.

The treatment was generally well tolerated, with 53% of patients experiencing pain improvement and 36% showing weight gain, while serious side effects like grade 3 anemia and neutropenia were relatively low, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Front-line treatment of inoperable or metastatic pancreatic cancer with gemcitabine and capecitabine: an intergroup, multicenter, phase II study. Stathopoulos, GP., Syrigos, K., Polyzos, A., et al.[2022]

The combination of galunisertib and gemcitabine showed an acceptable safety profile in a phase 1b study with 7 Japanese patients, as no dose-limiting toxicities were reported, although all patients experienced at least one treatment-emergent adverse event.

The treatment demonstrated preliminary efficacy, with a clinical response rate of 42.9% and a median progression-free survival of 64 days, indicating potential benefits for patients with advanced or metastatic pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of galunisertib in combination with gemcitabine in Japanese patients with metastatic or locally advanced pancreatic cancer. Ikeda, M., Takahashi, H., Kondo, S., et al.[2022]

In a study involving 239 patients aged 1 to 21 with newly diagnosed acute lymphoblastic leukemia (ALL), calaspargase pegol demonstrated similar efficacy to the standard pegaspargase, achieving comparable rates of complete remission (99% for pegaspargase vs. 95% for calaspargase).

Calaspargase, administered every 3 weeks, showed a significantly higher serum asparaginase activity at day 25 compared to pegaspargase (88% vs. 17% with therapeutic levels), while both treatments had similar toxicity profiles and 5-year event-free survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. Vrooman, LM., Blonquist, TM., Stevenson, KE., et al.[2021]

The combination of ipilimumab and gemcitabine was found to be safe and tolerable for treating advanced pancreatic ductal adenocarcinoma (PDAC), with a maximum tolerated dose established at ipilimumab 3 mg/kg and gemcitabine 1,000 mg/m2.

Despite the safety of the regimen, the overall response rate was only 14%, indicating that adding ipilimumab does not significantly enhance the effectiveness compared to gemcitabine alone in advanced PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study. Kamath, SD., Kalyan, A., Kircher, S., et al.[2022]

A patient with advanced pancreatic ductal adenocarcinoma harboring a V600E BRAF mutation showed an objective tumor response to a combination treatment of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib.

This case highlights the potential for targeted therapy in a small subset of pancreatic cancer patients, suggesting that BRAF mutations, although rare, may offer a new avenue for treatment beyond conventional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular Targeting of a BRAF Mutation in Pancreatic Ductal Adenocarcinoma: Case Report and Literature Review. Seghers, AK., Cuyle, PJ., Van Cutsem, E.[2021]

A new water-soluble form of curcumin, created by linking it to polyethylene glycol (PEG), significantly reduces pancreatic cancer cell growth more effectively than regular curcumin, suggesting improved efficacy as a cancer treatment.

This PEGylated curcumin not only inhibits cell proliferation by affecting the cell cycle and stabilizing tumor suppressor proteins but also enhances the effectiveness of gemcitabine, a common chemotherapy drug, making it a promising option for treating pancreatic adenocarcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polyethylene glycosylated curcumin conjugate inhibits pancreatic cancer cell growth through inactivation of Jab1. Li, J., Wang, Y., Yang, C., et al.[2022]

The study aimed to assess the safety and effectiveness of pegaspargase (PEG-ASP) combined with gemcitabine in patients with advanced metastatic solid tumors and lymphoma, involving 17 participants.

The trial was halted early due to concerns that the suggested doses of PEG-ASP would not maintain the necessary asparaginase levels for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter, open-label, Phase 1 study evaluating the safety and tolerability of pegaspargase in combination with gemcitabine in advanced metastatic solid tumors and lymphoma. Borad, MJ., Babiker, HM., Anthony, S., et al.[2022]

In the SEQUOIA study involving 567 patients with metastatic pancreatic ductal adenocarcinoma, adding pegilodecakin (PEG) to the FOLFOX chemotherapy regimen did not improve overall survival or progression-free survival compared to FOLFOX alone.

While the addition of PEG did not enhance efficacy, it was associated with manageable and tolerable safety profiles, with notable increases in certain immune markers, suggesting potential immunostimulatory effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase III Study of FOLFOX Alone or With Pegilodecakin as Second-Line Therapy in Patients With Metastatic Pancreatic Cancer That Progressed After Gemcitabine (SEQUOIA). Hecht, JR., Lonardi, S., Bendell, J., et al.[2022]

Galunisertib, when combined with gemcitabine, significantly improved overall survival in patients with unresectable pancreatic cancer, with median survival times of 8.9 months for the treatment group compared to 7.1 months for the placebo group.

The study demonstrated minimal added toxicity from galunisertib, suggesting it is a safe addition to standard chemotherapy, and identified specific biomarkers that may predict which patients could benefit most from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer. Melisi, D., Garcia-Carbonero, R., Macarulla, T., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11572257/

CASPER: A Phase I trial combining calaspargase pegol-mnkl ... This Phase I trial (NCT05034627) will evaluate the safety and tolerability of the MEK inhibitor, cobimetinib, in combination with pegylated L-asparaginase, L ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05034627

Study Details | NCT05034627 | Calaspargase Pegol-Mnkl ... Giving calaspargase pegol-mknl in combination with cobimetinib may help control the disease in patients with pancreatic cancer. Detailed Description. PRIMARY ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39378065/

CASPER: A Phase I trial combining calaspargase pegol-mnkl ... This Phase I trial (NCT05034627) will evaluate the safety and tolerability of the MEK inhibitor, cobimetinib, in combination with pegylated L-asparaginase.

4. moffitt.org moffitt.org/clinical-trials-and-studies/clinical-trial-23380/

Clinical Trial 23380 Histologically confirmed recurrent unresectable, locally advanced, or metastatic CRC, NSCLC, PANC, OVCA, MESO, or other solid tumors with MSLN expression.

5. clin.larvol.com clin.larvol.com/trial-detail/NCT05034627

Calaspargase Pegol-Mnkl and Cobimetinib for the ... Calaspargase Pegol-Mnkl and Cobimetinib for the Treatment of Locally Advanced or Metastatic Pancreatic Cancer. P1. OHSU Knight Cancer Institute.