Metastatic Pancreatic CancerPhase 1NCT01934634
Phase I Trial of LCL161 and Gemcitabine Plus Nab-Paclitaxel in Metastatic Pancreatic Cancer
A Phase 1 study testing LCL161, Gemcitabine and nab-Paclitaxel in people with Metastatic Pancreatic Cancer, run by US Oncology Research at 1 site in United States.
Trial summary
The goal of this study is to identify the maximum tolerated dose and dose-limiting side effects of LCL161 in combination with gemcitabine and nab-paclitaxel and to provide safety data in patients with measurable metastatic pancreatic cancer. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastatic Pancreatic Cancer
- What is being tested?
- LCL161, Gemcitabine and nab-Paclitaxel
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2014to Mar 2016
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients must provide written informed consent prior to any screening procedures.
- A signed Patient Authorization Form (HIPPA) has been obtained prior to registration.
- Age 18 years or older.
- Willing and able to comply with scheduled visits, treatment plan and laboratory tests
- Patient is able to swallow and retain oral medication.
- Histologically or cytologically documented measureable metastatic (Stage IV) pancreatic cancer with disease by computed tomography scan as defined by RECIST Version 1.1.
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- ECOG performance status 0-1.
- Required baseline laboratory status:
- Hemoglobin (Hgb) ≥ 90 g/L (9 g/dL)
- Platelets ≥ 100 x 109/L (100,000/mm3)
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (1500/mm3)
- Serum total bilirubin ≤ 1.5 x ULN (upper limit of normal)
- AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN, except for patients with tumor involvement of the liver who must have AST and ALT ≤ 5 x ULN
- Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 40 mL/min
- Patient did not receive previous treatment for Stage IV pancreatic cancer. Note: However, prior adjuvant treatment with fluorouracil or gemcitabine administered as a radiation sensitizer during and up to 4 weeks after radiation therapy is allowed. If patient received adjuvant therapy, tumor recurrence must have occurred ≥ 6 months after the last treatment.
Who cannot join
- Patient has any concurrent severe and/or uncontrolled medical conditions that could increase the patient's risk for toxicity while on the study or that could confound discrimination between disease- and study treatment-related toxicities.
- Patient has impaired cardiac function or clinically significant cardiac diseases, including any of the following:
- History or presence of ventricular tachyarrhythmia
- Presence of unstable atrial fibrillation (ventricular response > 100 bpm); Patients with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac exclusion criteria
- Patient is currently receiving chronic (> 14 days) treatment with corticosteroids at a dose ≥ 10 mg of prednisone (or its glucocorticoid equivalent) per day, or any other chronic immunosuppressive treatment that cannot be discontinued prior to starting study drug.
- Patient is currently receiving treatment with agents that are metabolized solely through CYP3A4/5 and have a narrow therapeutic index or are strong CYP2C8 inhibitors; or are receiving treatment with agents that carry a risk for QT prolongation and are CYP3A substrates. Caution should be used in patients taking other CYP2C8- or CYP3A4/5-interacting agents.
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- Patient has impairment of Gastrointestinal (GI) function or GI disease that may significantly alter the absorption of LCL161.
- Patient is a pregnant or breast feeding (lactating) woman, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive β-HCG laboratory test (> 5 mIU/mL).
- Patient is a woman of child-bearing potential, defined as all women physiologically capable of becoming pregnant and refusing to use highly effective methods of contraception during dosing and for 90 days after study treatment. Highly effective contraception methods include:
- Total abstinence or
- Male partner or female sterilization or
- Combination of any 2 of the following (a+b or a+c, or b+c):
- Use of oral, injected, or implanted hormonal methods of contraception
- Placement of an intrauterine device (IUD) or intrauterine system (IUS)
- Barrier methods of contraception: condom for male partner or occlusive cap (diaphragm or cervical/vault caps) with spermicidal form/gel/film/cream/ vaginal suppository.
- Note: Postmenopausal women are allowed to participate in this study. Women are considered postmenopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks earlier. In the case of oophorectomy alone, a woman is considered to be not of child bearing potential only when her reproductive status has been confirmed by follow-up hormone level assessment.
- Patient is abstaining from using a condom. Sexually active males must use a condom during intercourse while taking the drug and for 3 months after stopping study drug and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
- Patient has a history of lymphoma with or without treatment.
- Patient has a history of interstitial pneumonitis.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase I Trial of the Proapoptotic Agonist, LCL161, and Gemcitabine Plus Nab-Paclitaxel in Patients With Metastatic Pancreatic Cancer
The goal of this study is to identify the maximum tolerated dose and dose-limiting side effects of LCL161 in combination with gemcitabine and nab-paclitaxel and to provide safety data in patients with measurable metastatic pancreatic cancer.
Read the detailed description
Improved therapeutic options for advanced pancreatic adenocarcinoma treatment need to continue to be investigated. Since 1997, gemcitabine has been the agent of choice for first-line therapy in advanced pancreatic cancer, with a median survival of 5.7 months, and a 20% 1-year survival (Eli Lilly 1996). Combination therapies using gemcitabine as a backbone have been investigated, but none are superior to gemcitabine monotherapy, except for a modest increase in overall survival (OS) with erlotinib and gemcitabine (Moore et al 2007). In a study of FOLFIRINOX compared with gemcitabine as first-line therapy in 342 metastatic pancreatic cancer patients, median OS was 11.1 months in the FOLFIRINOX group and 6.8 months in the gemcitabine group; however, the FOLFIRINOX group experienced more adverse events particularly febrile neutropenia (Conroy et al 2011).
LCL161 is a biostable, cell-permeable, small molecular weight Smac-mimetic compound. It is an orally bioavailable pan-IAP inhibitor that demonstrates anti-tumor efficacy as a single agent in a small subset of cell lines, and in many more cell lines and xenograft models when given in combination with paclitaxel.
Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a formulation that is readily soluble in saline, eliminating the need for lipid-based solvents (ie, Cremophor EL) and corticosteroid and antihistamine premedications for hypersensitivity reactions required for traditional unbound paclitaxel. nab-paclitaxel has also been shown to actively bind to secreted protein acidic and rich in cysteine (SPARC) in the tumor stroma, which is highly expressed in pancreatic cancer and actively binds to the albumin in nab-paclitaxel and further concentrates the drug into the tumor. SPARC expression in the stroma of tumor cells has been associated with poor survival. In a Phase I/II trial (Von Hoff et al 2011) involving 67 patients with metastatic pancreatic adenocarcinoma, the regimen of nab-paclitaxel plus gemcitabine had tolerable adverse effects with substantial antitumor activity, warranting Phase III evaluation.
The Phase III study (MPACT) was a large, international study that determined that survival with nab-paclitaxel plus gemcitabine is superior to gemcitabine alone. nab-paclitaxel plus gemcitabine is a new standard for treatment of patients with metastatic pancreatic cancer (Von Hoff et al 2013). However, although this study shows promise for substantially improving OS in patients with pancreatic adenocarcinoma, insensitivity to these agents is likely to occur due to resistance to apoptosis, which has been observed in laboratory studies to occur for most of the cytotoxic agents used to treat pancreatic cancer in the past (Westphal and Kaltoff 2003). Exploitation of the apoptosis pathway may ultimately provide more effective, less toxic anticancer therapy that selectively circumvents treatment-resistant pathways.
Based on the above, there is a high likelihood that LCL161 in combination with nab-paclitaxel and gemcitabine will be determined to be safe and well tolerated, and will show substantial antitumor activity, warranting Phase II evaluation.
Up to 24 patients will be enrolled in Part A - Phase I Safety study. If the combination therapy is determined to be safe and well tolerated and shows substantial antitumor activity, a safety expansion cohort of 12 additional patients will be enrolled in Part B - Efficacy study to further confirm the tolerability and efficacy of LCL161 with an endpoint of complete response (CR).
- Conditions
- Metastatic Pancreatic Cancer
- Being tested
- LCL161, Gemcitabine, nab-Paclitaxel
- Keywords
- Pancreatic Cancer, Stage IV Pancreatic Cancer, Stage IV metastatic pancreatic ductal adenocarcinoma
- Medical subject headings
- Pancreatic Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LCL161Drug
LCL161 (tablets): 300, 600, 1200, or 1800 mg once a week (Day 1, 8, 15) for 3 weeks, every 28 days
GemcitabineDrug
Also called Gemzar
Gemcitabine IV: 1,000 mg/m2 once a week (Day 1, 8, 15) for 3 weeks, every 28 days
nab-PaclitaxelDrug
Also called Abraxane
nab-paclitaxel IV: 125 mg/m2 once a week (Day 1, 8, 15) for 3 weeks, every 28 days
| Study group | Role | What they receive |
|---|---|---|
| LCL161 +Gemcitabine +nab-Paclitaxel | Experimental | LCL161 (tablets): 600, 1200, or 1800 mg once a week (Day 1, 8, 15) for 3 weeks, every 28 days Gemcitabine IV: 1,000 mg/m2 once a week (Day 1, 8, 15) for 3 weeks, every 28 days nab-paclitaxel IV: 100 or 125 mg/m2 once a week (Day 1, 8, 15) for 3 weeks, every 28 days Receives: Drug: LCL161; Drug: Gemcitabine; Drug: nab-Paclitaxel |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum tolerated dose of LCL161
The maximum dose of LCL161 (tablets: 600, 1200, or 1800 mg once a week (Day 1, 8, 15) for 3 weeks, every 28 days) that is tolerated by the patients.
Measured: 1.6 years
Percentage of patients with Dose-Limiting Toxicities
The percentage of patients that have side effects that require dosage of LCL161 to be stopped or reduced.
Measured: 1.6 years
Secondary outcomes (1)
Objective Response Rate
Number of patients with Complete Response or Partial Response
Measured: 1.6 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Sep 2013 (estimated)
- Study startMar 2014
- Primary completionMar 2016 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metastatic Pancreatic CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 24 participants (estimated)
Sponsor and investigators
- Lead sponsor
- US Oncology Research
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Novartis Pharmaceuticals, Delta Clinical Research, LLC
- Responsible party
- Sponsor
- Investigators
- Yvonne M. Coyle, MD, Principal investigator, US Oncology Research, McKesson Specialty HealthCarlos H. Becerra, MD, Principal investigator, US Oncology Research, McKesson Specialty Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01934634
- Sponsor's protocol ID
- 12104
- Other IDs
- CLCL161AUS03T
- Status last verified
- Nov 2015
- First submitted
- 29 Aug 2013
- Last updated
- 10 Nov 2015
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 10 Nov 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Trial of the Proapoptotic Agonist, LCL161, and Gemcitabine Plus Nab-Paclitaxel in Patients With Metastatic Pancreatic Cancer
- ClinicalTrials.gov ID
- NCT01934634
- Acronym / sponsor ID
- 12104
- Conditions
- Metastatic Pancreatic Cancer
- Keywords
- Pancreatic Cancer, Stage IV Pancreatic Cancer, Stage IV metastatic pancreatic ductal adenocarcinoma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 24 participants (estimated)
- Lead sponsor
- US Oncology ResearchIndustry (pharma, biotech, devices)
- Collaborators
- Novartis Pharmaceuticals, Delta Clinical Research, LLC
- Study start
- Mar 2014
- Primary completion
- Mar 2016 (estimated)
- First posted
- 4 Sep 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this study is to identify the maximum tolerated dose and dose-limiting side effects of LCL161 in combination with gemcitabine and nab-paclitaxel and to provide safety data in patients with measurable metastatic pancreatic cancer.
Detailed description
Improved therapeutic options for advanced pancreatic adenocarcinoma treatment need to continue to be investigated. Since 1997, gemcitabine has been the agent of choice for first-line therapy in advanced pancreatic cancer, with a median survival of 5.7 months, and a 20% 1-year survival (Eli Lilly 1996). Combination therapies using gemcitabine as a backbone have been investigated, but none are superior to gemcitabine monotherapy, except for a modest increase in overall survival (OS) with erlotinib and gemcitabine (Moore et al 2007). In a study of FOLFIRINOX compared with gemcitabine as first-line therapy in 342 metastatic pancreatic cancer patients, median OS was 11.1 months in the FOLFIRINOX group and 6.8 months in the gemcitabine group; however, the FOLFIRINOX group experienced more adverse events particularly febrile neutropenia (Conroy et al 2011).
LCL161 is a biostable, cell-permeable, small molecular weight Smac-mimetic compound. It is an orally bioavailable pan-IAP inhibitor that demonstrates anti-tumor efficacy as a single agent in a small subset of cell lines, and in many more cell lines and xenograft models when given in combination with paclitaxel.
Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a formulation that is readily soluble in saline, eliminating the need for lipid-based solvents (ie, Cremophor EL) and corticosteroid and antihistamine premedications for hypersensitivity reactions required for traditional unbound paclitaxel. nab-paclitaxel has also been shown to actively bind to secreted protein acidic and rich in cysteine (SPARC) in the tumor stroma, which is highly expressed in pancreatic cancer and actively binds to the albumin in nab-paclitaxel and further concentrates the drug into the tumor. SPARC expression in the stroma of tumor cells has been associated with poor survival. In a Phase I/II trial (Von Hoff et al 2011) involving 67 patients with metastatic pancreatic adenocarcinoma, the regimen of nab-paclitaxel plus gemcitabine had tolerable adverse effects with substantial antitumor activity, warranting Phase III evaluation.
The Phase III study (MPACT) was a large, international study that determined that survival with nab-paclitaxel plus gemcitabine is superior to gemcitabine alone. nab-paclitaxel plus gemcitabine is a new standard for treatment of patients with metastatic pancreatic cancer (Von Hoff et al 2013). However, although this study shows promise for substantially improving OS in patients with pancreatic adenocarcinoma, insensitivity to these agents is likely to occur due to resistance to apoptosis, which has been observed in laboratory studies to occur for most of the cytotoxic agents used to treat pancreatic cancer in the past (Westphal and Kaltoff 2003). Exploitation of the apoptosis pathway may ultimately provide more effective, less toxic anticancer therapy that selectively circumvents treatment-resistant pathways.
Based on the above, there is a high likelihood that LCL161 in combination with nab-paclitaxel and gemcitabine will be determined to be safe and well tolerated, and will show substantial antitumor activity, warranting Phase II evaluation.
Up to 24 patients will be enrolled in Part A - Phase I Safety study. If the combination therapy is determined to be safe and well tolerated and shows substantial antitumor activity, a safety expansion cohort of 12 additional patients will be enrolled in Part B - Efficacy study to further confirm the tolerability and efficacy of LCL161 with an endpoint of complete response (CR).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| LCL161 +Gemcitabine +nab-Paclitaxel | Experimental | Drug: LCL161, Drug: Gemcitabine, Drug: nab-PaclitaxelLCL161 (tablets): 600, 1200, or 1800 mg once a week (Day 1, 8, 15) for 3 weeks, every 28 days Gemcitabine IV: 1,000 mg/m2 once a week (Day 1, 8, 15) for 3 weeks, every 28 days nab-paclitaxel IV: 100 or 125 mg/m2 once a week (Day 1, 8, 15) for 3 weeks, every 28 days |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- Patients must provide written informed consent prior to any screening procedures.
- A signed Patient Authorization Form (HIPPA) has been obtained prior to registration.
- Age 18 years or older.
- Willing and able to comply with scheduled visits, treatment plan and laboratory tests
- Patient is able to swallow and retain oral medication.
Key exclusion criteria (19 listed)
- Patient has any concurrent severe and/or uncontrolled medical conditions that could increase the patient's risk for toxicity while on the study or that could confound discrimination between disease- and study treatment-related toxicities.
- Patient has impaired cardiac function or clinically significant cardiac diseases, including any of the following:
- Patient is currently receiving chronic (> 14 days) treatment with corticosteroids at a dose ≥ 10 mg of prednisone (or its glucocorticoid equivalent) per day, or any other chronic immunosuppressive treatment that cannot be discontinued prior to starting study drug.
- Patient is currently receiving treatment with agents that are metabolized solely through CYP3A4/5 and have a narrow therapeutic index or are strong CYP2C8 inhibitors; or are receiving treatment with agents that carry a risk for QT prolongation and are CYP3A substrates. Caution should be used in patients taking other CYP2C8- or CYP3A4/5-interacting agents.
- Patient has impairment of Gastrointestinal (GI) function or GI disease that may significantly alter the absorption of LCL161.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LCL161LCL161 (tablets): 300, 600, 1200, or 1800 mg once a week (Day 1, 8, 15) for 3 weeks, every 28 days | Drug | LCL161 +Gemcitabine +nab-Paclitaxel |
| GemcitabineAlso: GemzarGemcitabine IV: 1,000 mg/m2 once a week (Day 1, 8, 15) for 3 weeks, every 28 days | Drug | LCL161 +Gemcitabine +nab-Paclitaxel |
| nab-PaclitaxelAlso: Abraxanenab-paclitaxel IV: 125 mg/m2 once a week (Day 1, 8, 15) for 3 weeks, every 28 days | Drug | LCL161 +Gemcitabine +nab-Paclitaxel |
Primary outcome
Maximum tolerated dose of LCL161
Time frame: 1.6 years
The maximum dose of LCL161 (tablets: 600, 1200, or 1800 mg once a week (Day 1, 8, 15) for 3 weeks, every 28 days) that is tolerated by the patients.
Percentage of patients with Dose-Limiting Toxicities
Time frame: 1.6 years
The percentage of patients that have side effects that require dosage of LCL161 to be stopped or reduced.
1 secondary outcome
Objective Response Rate
Time frame: 1.6 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Nov 2015.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Yvonne M. Coyle, MD principal investigator
US Oncology Research, McKesson Specialty Health
Carlos H. Becerra, MD principal investigator
US Oncology Research, McKesson Specialty Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing LCL161, Gemcitabine and nab-Paclitaxel in people with Metastatic Pancreatic Cancer, run by US Oncology Research at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 10 Nov 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum tolerated dose of LCL161 (time frame: 1.6 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Nov 2015.