Indolent LymphomaPhase 1NCT04431635
Dose De-escalation Study of the PI3k Alpha/Delta Inhibitor, Copanlisib Given in Combination With the Immunotherapeutic Agents, Nivolumab and Rituximab in Patients With Relapsed/Refractory Indolent Lymphoma
A Phase 1 study testing Copanlisib, Nivolumab and Rituximab in people with Indolent Lymphoma, run by University of Michigan Rogel Cancer Center at 5 sites in United States.
Trial summary
Patients with relapsed or refractory follicular or marginal zone lymphoma who have received at least one prior line of therapy will receive Copanlisib IV: day 1, 8, 15 every 28 days Nivolumab IV: Cycle 1 days 1 and 15; then day 1 only Rituximab IV: Cycle 1 days 1, 8, 15, 22; then day 1 (C2-6); then Q2 cycles (8-12) Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Indolent Lymphoma
- What is being tested?
- Copanlisib, Nivolumab and Rituximab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 5 sitesUnited States
- Study dates
- 15 Jun 2020to 14 Nov 2023
- 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
- Age ≥18 years at the time of informed consent.
- Diagnosis of relapsed or refractory indolent follicular or marginal zone lymphoma established by histologic assessment by a hematopathologist that has relapsed after at least one line of chemo-immunotherapy.
- Immunohistochemistry of the biopsy or
- Flow cytometry of the biopsy
- ECOG Performance Status ≤ 2
- Has an indication for treatment based on the presence of symptoms and/or GELF criteria as referenced in appendix A.
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- Must have failed or not be a candidate for an autologous stem cell transplantation.
- Women of childbearing potential must be willing to use appropriate contraception (barrier and hormonal therapy) or abstain from heterosexual activity from the point of registration through at least 12 months after the last dose of study drugs.
- -- NOTE: Women of childbearing potential are those who have not been surgically sterilized, have not been free of menses for ≥ 1 year, or her sole male partner has had a vasectomy at least 6 months prior to screening.
- Male subjects capable of fathering a child who have a female partner of childbearing potential must agree to use appropriate method(s) of contraception or abstain from heterosexual activity starting with the first dose of study drug through 1 month after the last dose of the study drugs.
- Adequate organ function defined as
- Hepatic:
- Total Bilirubin ≤ 1.5 mg/dL
- AST and ALT ≤ 2.5 x ULN.
- Renal: Creatinine < 2.0 mg/dl or CrCL > 30 mL/minute
- Bone marrow function:
- ANC ≥ 1000/mm3 (500/mm3 if known bone marrow (BM) involvement)
- Platelet ≥ 75,000/mm3 (or 50,000/mm3 if known BM involvement)
- Hgb > 9 g/dL (transfusions allowed to meet this criterion)
- Adequate glycemic control as demonstrated by a baseline fasting blood sugar (BS) ≤ 150 mg/dL. If uncontrolled then patient must be referred to PCP or endocrinology for medical management. Patient may be enrolled if adequate control is obtained prior to day 1 of therapy.
- Adequate blood pressure (BP) control as demonstrated by a baseline BP of < 150/90. If uncontrolled then patient must be referred to PCP for medical management. Patient may be enrolled if adequate control is obtained prior to day 1 of therapy.
- Prior treatment is allowed if
- at least 4 weeks must have elapsed since last chemotherapy and/or radiation and the patient has recovered to ≤ grade 1 toxicity from all treatment related events.
- at least 3 months must have passed since radio-immunotherapy.
- at least 3 months have passed since date of stem cell infusion (autograft) and patient has recovered to ≤ grade 1 toxicities related to this procedure.
- Prior treatment with a PD-1/PD-L1 and/or PI3K inhibitor is allowed unless patient prior treatment was discontinued for intolerance.
Who cannot join
- Pregnant or breastfeeding women. NOTE: Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to study registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. NOTE: Breast milk cannot be stored for future use while the mother is being treated on study.
- Diagnosis of follicular grade 3b, post-transplant lymphoproliferative disorder (PTLD), or presence of histologic transformation.
- Subjects with LFT abnormalities at baseline (above values per inclusion criteria), history of cirrhotic liver morphology or alcoholic cirrhosis, subjects who use acetaminophen at doses in excess of 2 g every day and have evidence of compromised hepatic reserve.
- Primary or metastatic CNS disease prior to study enrollment
- Uncontrolled current illness, including, but not limited to ongoing or active infections, symptomatic congestive heart failure, unstable angina pectoris, unstable cardiac arrhythmia, evidence of interstitial lung disease or active, noninfectious pneumonitis including symptomatic and/or pneumonitis requiring treatment and/or psychiatric illness or social situations that would limit compliance with study requirements.
- History of inflammatory bowel disease i.e. Crohn's disease, ulcerative colitis.
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- HIV infection. NOTE: HIV testing is required.
- Active infection with Hepatitis B or C virus (defined as a positive Hepatitis B surface antigen/ positive Hepatitis C antibody or detectable viral load by PCR). Patients with positive antibody but negative viral loads will be eligible for study participation but will require appropriate prophylaxis.
- NOTE: Hepatitis B and C testing are required.
- Screening rate-corrected (using Friderica's correction) QT interval (QTcF) must not be > 480 msec via a standard 12-lead ECG within 28 days prior to registration.
- Concomitant therapy in the last 4 weeks of any of the following: cytotoxic chemotherapy, immunosuppressive agents, other investigational therapies, or chronic use of systemic corticosteroids (doses ≤ 10 mg/day prednisone or equivalent are permitted).
- Active or prior documented autoimmune or inflammatory disorders within the past 3 years prior to study registration. The following are exceptions to this criterion:
- Subjects with vitiligo or alopecia
- Subjects with hypothyroidism (eg. following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment.
- Known allergy or reaction to any component of either study drug formulation.
- Prior allogeneic stem cell transplant.
- Receipt of live attenuated vaccine within 30 days before the first dose of study treatment.
- HbA1c > 8.5% at Screening
- Patient that require treatment with agents that are CYP3A4 inhibitors or strong CYP3A4 inducers. Patients who are on agents that fall into this category must be off for at least two weeks prior to start of treatment.
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
United States5 sites
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, 48109
University of Michigan Health System
Ann Arbor, Michigan, 48109
University of Illinois Cancer Center
Chicago, Illinois, 60612
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, 08903
University of Nebraska Medical Center
Omaha, Nebraska, 68198
About this study
Official title: Phase IB Dose De-escalation Study of the PI3k Alpha/Delta Inhibitor, Copanlisib Given in Combination With the Immunotherapeutic Agents, Nivolumab and Rituximab in Patients With Relapsed/Refractory Indolent Lymphoma.Big Ten Cancer Research Consortium BTCRC-LYM17-145
Patients with relapsed or refractory follicular or marginal zone lymphoma who have received at least one prior line of therapy will receive
- Copanlisib IV: day 1, 8, 15 every 28 days
- Nivolumab IV: Cycle 1 days 1 and 15; then day 1 only
- Rituximab IV: Cycle 1 days 1, 8, 15, 22; then day 1 (C2-6); then Q2 cycles (8-12)
Read the detailed description
Patients with relapsed/refractory lymphoma generally have few if any curative options and demonstrate poor response rates to standard salvage therapies. Novel regimens utilizing molecular targets are needed to improve outcomes in this patient population. While studies evaluating single agent small-molecule inhibitors have demonstrated activity in this setting, combinations of these drugs are generally thought to be more efficacious due to targeting separate mechanisms of action and decreased chance of developing resistance. The PD-1/PD-L1 axis is a molecular target that has been demonstrated to be up-regulated in several tumors including malignant lymphoma. Several pre-clinical studies have demonstrated the importance of this axis on clinical outcomes of patients afflicted with low grade lymphoma including FL. Targeting this axis with specific inhibitors would appear to be a rationale way to improve outcomes in patients afflicted with these diseases. PI3K inhibitors in addition to inhibiting signaling, impart changes in the immune cells in the tumor microenvironment and would appear to be a logical candidate to explore in combination with immunotherapy. Based on these preliminary data, we believe that we have justification for proceeding with our proposed phase I study to combine the PD-1 inhibitor, nivolumab, with the PI3K inhibitor, copanlisib, and the CD20 antibody, rituximab, in patients with relapsed/refractory follicular and marginal zone lymphoma. This work has the potential to provide a novel strategy to improve upon the clinical response noted in this patient population.
- Conditions
- Indolent Lymphoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CopanlisibDrug
Copanlisib IV: day 1, 8, 15 every 28 days
NivolumabDrug
Nivolumab IV: Cycle 1 days 1 and 15; then day 1 only
RituximabDrug
Rituximab IV: Cycle 1 days 1, 8, 15, 22; then day 1 (C2-6); then Q2 cycles (8-12)
| Study group | Role | What they receive |
|---|---|---|
| Arm A: Copanlisib, Nivolumab & Rituximab | Experimental | Copanlisib IV: day 1, 8, 15 every 28 days Nivolumab IV: Cycle 1 days 1 and 15; then day 1 only Rituximab IV: Cycle 1 days 1, 8, 15, 22; then day 1 (C2-6); then Q2 cycles (8-12) Receives: Drug: Copanlisib; Drug: Nivolumab; Drug: Rituximab |
What is being measured
The primary outcome is the main question the study is designed to answer.
MTD (Maximum Tolerated Dose) of copanlisib given in combination with nivolumab and rituximab
To estimate the MTD (Maximum Tolerated Dose) of copanlisib given in combination with nivolumab and rituximab
Measured: 28 days
Complete Response rate of the combination of copanlisib, nivolumab, and rituximab given at the MTD.
To estimate the Complete Response (CR) rate of the combination of copanlisib, nivolumab, and rituximab given at the MTD as determined by Lyric criteria [Cheson 2016}
Measured: 1 year
Secondary outcomes (5)
Summarize Adverse Events
Summarize all adverse events graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Measured: Up to two years
Overall Response
The rate of overall response, defined as either CR or PR within 1 year of initiation of therapy.
Measured: 1 year
Duration of Response
- Duration of response, as calculated from the time of initial response (CR or PR, determined by Lyric criteria [Cheson 2016]) until disease progression or death due to any cause (whichever occurs first).
Measured: Up to two years
Progression Free Survival
- Progression free survival, as calculated from the first dose of the combination to the occurrence of definitive disease progression (as defined by Cheson 2016) or death from any cause, whichever comes first.
Measured: Up to two years
Time to Next Treatment
Time to next treatment (TTNT) is defined as the time from end of primary treatment to institution of next therapy.
Measured: Up to two years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jun 2020
- Study start15 Jun 2020
- Primary completion14 Nov 2023
- Study completion14 Nov 2023
Why it stopped: Loss of study funding
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Indolent LymphomaStudies of the same condition, open and under way.
- More trials run by University of Michigan Rogel Cancer CenterThe sponsor's other registered studies.
- 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
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Michigan Rogel Cancer Center
- Sponsor type
- University, hospital or other
- Collaborators
- Bayer, Bristol-Myers Squibb, University of Michigan, Big Ten Cancer Research Consortium
- Responsible party
- Sponsor
- Investigators
- Yasmin H Karimi, MD, Principal investigator, The University of Michigan Rogel Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04431635
- Sponsor's protocol ID
- UMCC 2019.097
- Other IDs
- BTCRC-LYM17-145, HUM00166647
- Status last verified
- Sep 2024
- First submitted
- 11 Jun 2020
- Last updated
- 27 Sep 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase IB Dose De-escalation Study of the PI3k Alpha/Delta Inhibitor, Copanlisib Given in Combination With the Immunotherapeutic Agents, Nivolumab and Rituximab in Patients With Relapsed/Refractory Indolent Lymphoma.Big Ten Cancer Research Consortium BTCRC-LYM17-145
- ClinicalTrials.gov ID
- NCT04431635
- Acronym / sponsor ID
- UMCC 2019.097
- Conditions
- Indolent Lymphoma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Loss of study funding
- Enrolment
- 6 participants (actual)
- Lead sponsor
- University of Michigan Rogel Cancer CenterUniversity, hospital or other
- Collaborators
- Bayer, Bristol-Myers Squibb, University of Michigan, Big Ten Cancer Research Consortium
- Study start
- 15 Jun 2020 (actual)
- Primary completion
- 14 Nov 2023 (actual)
- Study completion
- 14 Nov 2023 (actual)
- First posted
- 16 Jun 2020 (actual)
- 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.
Patients with relapsed or refractory follicular or marginal zone lymphoma who have received at least one prior line of therapy will receive
- Copanlisib IV: day 1, 8, 15 every 28 days
- Nivolumab IV: Cycle 1 days 1 and 15; then day 1 only
- Rituximab IV: Cycle 1 days 1, 8, 15, 22; then day 1 (C2-6); then Q2 cycles (8-12)
Detailed description
Patients with relapsed/refractory lymphoma generally have few if any curative options and demonstrate poor response rates to standard salvage therapies. Novel regimens utilizing molecular targets are needed to improve outcomes in this patient population. While studies evaluating single agent small-molecule inhibitors have demonstrated activity in this setting, combinations of these drugs are generally thought to be more efficacious due to targeting separate mechanisms of action and decreased chance of developing resistance. The PD-1/PD-L1 axis is a molecular target that has been demonstrated to be up-regulated in several tumors including malignant lymphoma. Several pre-clinical studies have demonstrated the importance of this axis on clinical outcomes of patients afflicted with low grade lymphoma including FL. Targeting this axis with specific inhibitors would appear to be a rationale way to improve outcomes in patients afflicted with these diseases. PI3K inhibitors in addition to inhibiting signaling, impart changes in the immune cells in the tumor microenvironment and would appear to be a logical candidate to explore in combination with immunotherapy. Based on these preliminary data, we believe that we have justification for proceeding with our proposed phase I study to combine the PD-1 inhibitor, nivolumab, with the PI3K inhibitor, copanlisib, and the CD20 antibody, rituximab, in patients with relapsed/refractory follicular and marginal zone lymphoma. This work has the potential to provide a novel strategy to improve upon the clinical response noted in this patient population.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Arm A: Copanlisib, Nivolumab & Rituximab | Experimental | Drug: Copanlisib, Drug: Nivolumab, Drug: RituximabCopanlisib IV: day 1, 8, 15 every 28 days Nivolumab IV: Cycle 1 days 1 and 15; then day 1 only Rituximab IV: Cycle 1 days 1, 8, 15, 22; then day 1 (C2-6); then Q2 cycles (8-12) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (26 listed)
- Age ≥18 years at the time of informed consent.
- Diagnosis of relapsed or refractory indolent follicular or marginal zone lymphoma established by histologic assessment by a hematopathologist that has relapsed after at least one line of chemo-immunotherapy.
- ECOG Performance Status ≤ 2
- Has an indication for treatment based on the presence of symptoms and/or GELF criteria as referenced in appendix A.
- Must have failed or not be a candidate for an autologous stem cell transplantation.
Key exclusion criteria (19 listed)
- Pregnant or breastfeeding women. NOTE: Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to study registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. NOTE: Breast milk cannot be stored for future use while the mother is being treated on study.
- Diagnosis of follicular grade 3b, post-transplant lymphoproliferative disorder (PTLD), or presence of histologic transformation.
- Subjects with LFT abnormalities at baseline (above values per inclusion criteria), history of cirrhotic liver morphology or alcoholic cirrhosis, subjects who use acetaminophen at doses in excess of 2 g every day and have evidence of compromised hepatic reserve.
- Primary or metastatic CNS disease prior to study enrollment
- Uncontrolled current illness, including, but not limited to ongoing or active infections, symptomatic congestive heart failure, unstable angina pectoris, unstable cardiac arrhythmia, evidence of interstitial lung disease or active, noninfectious pneumonitis including symptomatic and/or pneumonitis requiring treatment and/or psychiatric illness or social situations that would limit compliance with study requirements.
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 |
|---|---|---|
| CopanlisibCopanlisib IV: day 1, 8, 15 every 28 days | Drug | Arm A: Copanlisib, Nivolumab & Rituximab |
| NivolumabNivolumab IV: Cycle 1 days 1 and 15; then day 1 only | Drug | Arm A: Copanlisib, Nivolumab & Rituximab |
| RituximabRituximab IV: Cycle 1 days 1, 8, 15, 22; then day 1 (C2-6); then Q2 cycles (8-12) | Drug | Arm A: Copanlisib, Nivolumab & Rituximab |
Primary outcome
MTD (Maximum Tolerated Dose) of copanlisib given in combination with nivolumab and rituximab
Time frame: 28 days
To estimate the MTD (Maximum Tolerated Dose) of copanlisib given in combination with nivolumab and rituximab
Complete Response rate of the combination of copanlisib, nivolumab, and rituximab given at the MTD.
Time frame: 1 year
To estimate the Complete Response (CR) rate of the combination of copanlisib, nivolumab, and rituximab given at the MTD as determined by Lyric criteria [Cheson 2016}
5 secondary outcomes
Summarize Adverse Events
Time frame: Up to two years
Overall Response
Time frame: 1 year
Duration of Response
Time frame: Up to two years
Progression Free Survival
Time frame: Up to two years
Time to Next Treatment
Time frame: Up to two years
Results and safety
The study was stopped early (reason given: Loss of study funding). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Sep 2024.
- Individual participant dataSharing planned: No
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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.
Yasmin H Karimi, MD principal investigator
The University of Michigan Rogel Cancer Center
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Copanlisib, Nivolumab and Rituximab in people with Indolent Lymphoma, run by University of Michigan Rogel Cancer Center at 5 sites 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 26 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: stopped early, as of the sponsor's last update on 27 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites 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?
The study was stopped early (reason given: Loss of study funding). 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?
MTD (Maximum Tolerated Dose) of copanlisib given in combination with nivolumab and rituximab (time frame: 28 days). 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 27 Sep 2024.