Randomized Phase II Trial of Single Agent MEK Inhibitor Trametinib (GSK1120212) Vs 5-Fluorouracil or Capecitabine in Refractory Advanced Biliary Cancer
PRIMARY OBJECTIVES:
I. To assess overall survival (OS) in patients with refractory advanced biliary cancer
randomized to Arm 1: trametinib compared to those randomized to Arm 2: chemotherapy (either
5-fluorouracil [fluorouracil] and leucovorin [leucovorin calcium] or capecitabine).
SECONDARY OBJECTIVES:
I. To determine the frequency and severity of adverse events of trametinib in this patient
population.
II. To assess response rate (RR) and progression-free survival (PFS) in patients randomized
to Arm 1: trametinib and patients randomized to Arm 2: chemotherapy (fluorouracil [5-FU] or
capecitabine in this patient population).
TERTIARY OBJECTIVES:
I. To determine if a 16-gene expression signature is predictive of mitogen-activated protein
kinase kinase (MEK) efficacy as evidenced by improved RR, PFS, and OS.
II. To evaluate the effects of trametinib on the inflammatory cytokine and explore potential
associations with response rate and survival.
III. To estimate lean soft tissue and fat mass weight gain as a result of treatment with
trametinib vs. capecitabine in patients with advanced refractory biliary cancer.
IV. To bank tissue samples for other future correlative studies including next generation
sequencing and whole genome methylation assays. NOTE: These potential future correlative
studies will not be performed until an amended protocol with relevant detailed information
including specific arms and assays is approved by Cancer Therapy Evaluation Program (CTEP).
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive trametinib orally (PO) once daily (QD) on days 1-21. Courses repeat
every 21 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive 1 of 2 treatment regimens at the discretion of the investigator.
ARM IIA: Patients receive leucovorin calcium intravenously (IV) over 2 hours and fluorouracil
IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.
ARM IIB: Patients receive capecitabine PO twice daily (BID) on days 1-14. Courses repeat
every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years.
An Open-label, Randomized, Phase III Study Comparing 177Lu-PSMA-617 in Combination With Standard of Care, Versus Standard of Care Alone, in Adult Male Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC)
In this international, open-label, prospective, phase III study, where approximately 1126
patients with treatment naïve or minimally treated PSMA-positive mHSPC will be randomized in
a 1:1 ratio to receive Standard of Care (SoC) with or without the radioligand 177Lu-PSMA-617.
The primary objective of the study is to determine whether the combination of 177Lu-PSMA-617
+ SoC improves rPFS over that obtained by administration of SoC alone in mHSPC patients.
The randomization will be stratified according to the following three factors: disease volume
(high v low), age >= 70 years (yes/no), and on Previous or planned treatment (prostatectomy
or radiation) to primary (prostate) tumor (yes/no).
Study duration: approximately 50 months. screening period: after signing ICF, patients will
be assessed for eligibility and will be scanned with 68Ga PSMA-11 to identify PSMA expression
status. Following completion of all required screening procedures and verifying participant
eligibility, the participant will be randomized via the interactive response technology (IRT)
system.
Amended protocol v02 included an option for participants to be enrolled into a separate
long-term safety follow-up study, and China extension cohort (40 to 60 participants). Amended
protocol v03 excluded China extension cohort and added a second 68Ga-PSMA-11 PET/CT scan at
rPD.
Prior treatment:
- Up to 45 days of LHRH agonist/antagonists is allowed prior to ICF signature. If patient
did not start the ADT prior randomization, ADT should start as soon as possible and
ideally no later than 2 weeks after randomization.
- Up to 45 days of ARDT is allowed prior ICF signature. If patient did not start the ARDT
prior randomization, ARDT should start as soon as possible and ideally no later than 2
weeks after randomization. Patients will received ARDT as per label instructions.
Randomization period:
The participant will be randomized in a 1:1 ratio to receive Standard of Care (SoC) with or
without the radioligand 177Lu-PSMA-617.
Treatment period:
Patients randomized to the investigational arm (i.e. SoC+177Lu-PSMA-617): Patients will
receive SoC as per label instructions, after randomization, if not started earlier and in the
time frame allowed by the protocol. Patients must begin 177Lu-PSMA-617 dosing within 14 days
after randomization or as soon as possible after the product is received. 177Lu-PSMA-617 is
administered at the dose of 7.4 GBq (+/- 10%), once every 6 weeks (+/- 1 week) for a planned
6 cycles.
Patients randomized to the control arm will begin receiving SoC as per label instructions
after randomization, if not started earlier and in the time frame allowed by the protocol.
The primary endpoint of rPFS will be assessed by a centralized blinded image review committee
(i.e., BIRC) using radiographic images provided by the treating physician.
Participants from both arms will also undergo PET/CT scan with 68GaPSMA-11 following
Centrally confirmed rPD.
An end of treatment (EOT) visit will be performed when participants permanently discontinue
study treatment.
Cross-over period:
After patients randomized to the SoC alone (i.e., control) arm experience radiographic
progression (the rPFS event) as confirmed by BIRC, they will be allowed to cross-over to
receive 177Lu-PSMA-617 +/- SoC per the discretion of the treating physician. If cross-over to
177Lu-PSMA-617 is selected, then 177Lu-PSMA-617 will be administered with the same
dose/schedule as participants who were initially randomized to receive 177Lu-PSMA-617 as
described above. Study cross-over participants for whom 177Lu-PSMA-617 is discontinued must
have a second End of Treatment (EOT2) visit performed =< 7 days and enter the Post-treatment
Follow-up .
Post-Treatment Follow-Up (Safety, Efficacy):
After treatment discontinuation, all participants will be followed for safety with a 30-day
safety follow-up visit (FUP) as well as longer term safety follow-up assessments for a period
of approximately 12 months.
Participants who discontinue study treatment without having progressive disease confirmed by
BIRC, will continue to be assessed for efficacy (efficacy follow-up) during the
post-treatment follow-up period until the occurrence of their BIRC-confirmed radiographic
disease progression (rPFS) event , or if the total number of protocol-defined rPFS events has
occurred triggering the primary analysis, whichever occurs first.
Survival Follow-Up:
After study treatment discontinuation, or post-treatment follow-up period discontinuation,
the participant's status will be collected every 90 days (via phone calls) as part of the
survival follow-up. Every effort should be made to comply with the survival follow-up
schedule and ensure collection of participant survival. The survival follow-up and the study
will end when the number of OS events required for final OS analysis will be reached.
A Phase 2 Multicenter Study of Autologous Tumor Infiltrating Lymphocytes (TIL or LN-145) in Patients With Metastatic Non-Small-Cell Lung Cancer
LN-145 is a ready-to-infuse TIL therapy that utilizes an autologous TIL manufacturing
process, as originally developed by the NCI and further optimized by Iovance for the
treatment of patients with metastatic NSCLC. The cell transfer therapy used in this study
involves patients receiving a non-myeloablative (NMA) lymphodepleting preparative regimen,
followed by infusion of autologous TIL, then finally followed by the administration of IL-2.
A Randomized, Controlled Phase 3 Study of Pacritinib Versus Physician's Choice in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis With Severe Thrombocytopenia (Platelet Count <50,000/μL)(PACIFICA)
The study is a randomized, controlled phase 3 study comparing the efficacy of pacritinib with
P/C therapy in patients with PMF, PPV-MF, or PET-MF (Dynamic International Prognostic Scoring
System [DIPSS] risk score of Intermediate-1 to High-Risk), who have had had no or limited
exposure to any JAK2 inhibitor or are JAK2 inhibitor-naive, and who have severe
thrombocytopenia (platelet count <50,000/µL). This study was designed to use the pacritinib
200 mg BID dose, which was determined to be the optimal dose based on dose- and
exposure-response analyses conducted using all available data, including the dosing data from
the previous portion of this study. Patients will be randomized 2:1 to receive pacritinib 200
mg BID or the P/C therapy (limited to single drugs from the following list: corticosteroids,
hydroxyurea, danazol, or low-dose ruxolitinib). The proposed P/C regimen for a patient must
be selected prior to randomization. Randomization will be stratified by prior JAK2 inhibitor
therapy (yes/no) and P/C therapy selected prior to randomization. Prior JAK2 inhibitor
therapy will be defined as any duration of treatment with a JAK2 inhibitor, such as
ruxolitinib, fedratinib, or momelotinib. To be eligible, patients are not allowed to have
been treated with more than one JAK2 inhibitor. Assigned treatment will continue until the
patient experiences progressive disease or intolerable AEs, withdraws consent, or initiates
new MF-directed therapy. No study treatment crossover will be allowed at any time. All
patients should complete all visit procedures through Week 24, including patients who stop
treatment or have protocol-defined progressive disease prior to Week 24, unless the patient
withdraws consent for study procedures, dies, undergoes splenic irradiation or splenectomy,
initiates any non-protocol-directed anti-MF treatment, or the study is terminated. In
addition to the above, patients will be considered to have discontinued treatment if
pacritinib or P/C therapy is held for >28 consecutive days due to treatment toxicity, or if
treatment is discontinued for lack of efficacy, or at the request of the principal
investigator or the patient. Following the Week 24 assessment, patients who are benefiting
from therapy will be allowed to continue receiving the assigned treatment (pacritinib or P/C)
until the patient experiences progressive disease, intolerable AEs, withdraws consent, or
initiates new MF-directed therapy. All randomized patients will be followed for survival for
2.5 years from the date of randomization unless consent for follow-up is withdrawn.
A Phase 1/2 Study of EG-70 as an Intravesical Administration to Patients With BCG Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC) and High-Risk NMIBC Patients Who Are BCG Naïve or Received Incomplete BCG Treatment
EG-70 is a novel non-viral gene therapy. EG-70 is designed to elicit a local immune response
following delivery of the study gene therapy to the bladder urothelium. This approach of
local administration through bladder instillation has the potential to induce a potent immune
response exclusively at the site of the tumor, resulting in greater therapeutic benefit while
reducing undesirable systemic toxicity.
Eligible BCG-unresponsive NMIBC patients will be enrolled in Phase 1, and Cohort 1 of Phase
2. Eligible high-risk NMIBC patients who have been incompletely treated or are BCG-naïve will
be enrolled starting in Phase 2 in a separate single-arm cohort (Cohort 2).
Patients will be treated for up to four 12-week cycles of study drug instillation doses and
assessments with follow up assessments.
A Phase 1b Dose-Escalation Study of Cabozantinib (XL184) Administered Alone or in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors
- Dose Escalation Stage: to determine the schedule and maximum tolerated dose (MTD) and/or
recommended Expansion Stage dose of cabozantinib when taken in combination with a
standard dosing regimen of atezolizumab (1200 mg infusion, once every 3 weeks).
- Expansion Stage: to determine the preliminary efficacy (objective response rate [ORR]
per RECIST 1.1) and safety of the recommended combination dose of cabozantinib with
atezolizumab in eighteen tumor-specific cohorts including subjects with advanced UC,
RCC, CRPC, NSCLC, TNBC, OC, EC, HCC, GC/GEJC/LEC, CRC, H&N, and DTC.
- Exploratory SAC Cohorts: Descriptive efficacy, safety, PK, and biomarker analyses of
single-agent cabozantinib in UC, NSCLC, and CRPC subjects. Descriptive efficacy and
safety analyses of combination therapy after progression on single-agent therapy
- Exploratory SAA Cohort: Descriptive efficacy, safety, PK, and biomarker analyses of
single-agent atezolizumab in CRPC subjects. Descriptive efficacy and safety analyses of
combination therapy after progression on single-agent therapy
A Phase 1b/2 Open Label Umbrella Study of Sasanlimab Combined With Anti-Cancer Therapies Targeting Multiple Molecular Mechanisms in Participants With Non-Small Cell Lung Cancer (NSCLC)
Landscape 1011 is a clinical research study for people with advanced (stage 3b or 4)
non-small cell lung cancer (NSCLC). The purpose of this study is to learn if the study
medicine (sasanlimab, a type of immunotherapy) along with other study medicines is safe and
effective in people with non-small cell lung cancer that has spread outside of the lungs.
There are currently two sub-studies using different types of medicines. People in the first
sub-study will receive sasanlimab as a subcutaneous (under the skin) injection at the study
clinic every 4 weeks. Additionally, they will take targeted cancer therapies encorafenib by
mouth once a day and binimetinib by mouth twice a day at home.
People in the second sub-study will receive the study medicine sasanlimab as a subcutaneous
(under the skin) injection at the study clinic every 3 weeks and will also receive SEA-TGT
(an immunotherapy) by infusion every three weeks.
Additionally, they will take axitinib (a targeted therapy) by mouth twice a day at home.
In addition to taking the study drugs, participants in the sub-studies will be asked to visit
the clinic for health checks. These include health questions, physical examinations, blood
and urine samples, and imaging scans. These assessments help the study doctor and team to
monitor the participants' safety and well-being, and to see how their cancer is responding to
the treatment. Participants will continue in the study until the cancer is no longer
responding to the study medicine.
A Phase I/II, Multicenter, Open-Label Study of Nous-209 Genetic Vaccine for the Treatment of Microsatellite Unstable Solid Tumors
Ref: Protocol v9.0, dated 7Nov2023. Both Frame Shift Peptide (FSP) neoantigen-encoding
genetic vaccines are administered intramuscularly using 1 prime with the GAd20-209-FSP and 3
boosts with MVA-209-FSP in combination with Keytruda®, the licensed programmed death
receptor-1 (PD-1)-blocking antibody pembrolizumab, in adult subjects with unresectable or
metastatic Mismatch Repair Deficient (dMMR) or MSI-H colorectal cancer (CRC), gastric, or G-E
junction tumors. In Phase I, GAd20-209-FSP prime will be administered on the day of 2nd
pembrolizumab infusion (week 4); MVA-209-FSP boosts will be administered on the day of 3rd,
4th and 5th pembrolizumab infusion (weeks 7 and 10 and 13). In Phase II, GAd20-209-FSP prime
will be administered on the same day as the 1st pembrolizumab infusion (day 1, week 1);
MVA-209-FSP boosts will be administered in week 2 and at the time of the 2nd and 3rd
pembrolizumab infusions (weeks 4 and 7).
The study is composed of a Phase I divided in two parts and a Phase II, as described below :
Phase I:
- Cohort A - Dose escalation Cohort of Nous-209 vaccine plus pembrolizumab combination
therapy in adult subjects with unresectable or metastatic deficient mismatch repair
(dMMR) or MSI-H CRC, gastric, or gastro-esophageal junction (G-E junction) tumors;
- Cohort B - Expansion Cohort at Recommended Phase 2 Dose (RP2D) of Nous-209 vaccine plus
pembrolizumab combination therapy in adult subjects with unresectable or metastatic dMMR
or MSI-H CRC, gastric, or G-E junction tumors. Part 2 - Extended Follow-up from week 27
to week 110.
Phase I (Cohorts A and B): The Sponsor estimates that the trial will require approximately 24
months from the time the first subject signs the informed consent until the last subject's
last visit at week 26 (Main Study); and approximately 42 months until last subject's last
visit at week 110 (Extended follow up).
Phase II:
Expansion at RP2D of Nous-209 vaccine plus Keytruda® (pembrolizumab) combination therapy in
adult subjects in the following study population:
- Cohort C (Phase II) - Subjects with locally advanced unresectable or metastatic,
microsatellite instability high (MSI-H) or dMMR CRC who are eligible for anti-PD-1 1st
line of treatment. Subjects will be randomized with an allocation ratio 2:1 to Nous-209
vaccine plus pembrolizumab combination therapy versus pembrolizumab monotherapy.
- Cohort D (Phase II) - Subjects with locally advanced unresectable or metastatic,
microsatellite instability high (MSI-H) or dMMR CRC who have had radiographic
progression (PD) after having a best response of stable disease (SD) or better on/after
anti-PD1 treatment.
Phase II (Cohorts C and D): Participation duration per subject is expected to last up to 18
months in Cohort C and up to 12 months in Cohort D.
Subjects who do not progress might stay in extended follow-up for up to approximately 2 years
(106 weeks or completion of 35 administrations of pembrolizumab).
Enrollment in Phase I is now terminated, and in Phase II is ongoing.
A Phase 1-2 Study of the Safety, Pharmacokinetics, and Activity of ASTX029 in Subjects With Advanced Solid Tumors
ASTX029 is a synthetic small molecule inhibitor of extracellular signal-regulated kinases
(ERKs) 1/2. ASTX029 has not been previously evaluated in human subjects. The Phase 1 portion
of this study will assess safety and determine the maximum tolerated dose, the recommended
Phase 2 dose (RP2D), and the recommended dosing regimen of ASTX029 administered orally. The
Phase 2 portion will assess preliminary clinical activity in tumors characterized by gene
aberrations in the mitogen-activated protein kinase (MAPK) signal pathway that may confer
sensitivity to ASTX029.
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